APPLI

PREC ISION

OPHT H A LMOLOG Y TM ED2020 GENE TICS A G

APPLIED TCATTCTATTCGGTTTACACGGCGGTAACCTTAACACTCAG CAGCATCATTCATTTCGGTTTACACGATCCAGAGTGCGGTAT

C T G

The Department of At the same time, we train ophthalmologists Aat Columbia University Irving Medical Center and researchers to be the future leaders is a leading international center for the in the field. We have successfully developed

management of sight-threatening disorders new drugs, devices and procedures to

and scientific exploration to elucidate enhance the lives of our patients and have CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACACTCAG CAGCATCATTCATTTCGGTTTACACGATCCAGAGTGCGGTAACCTTAACCTAGC disease mechanisms and discover novel launched the Applied Genetics Initiative

treatments. These aspirations are realized at Columbia Ophthalmology. That

through seamless collaborations between our groundbreaking tradition continues today

outstanding, compassionate and with Precision Ophthalmologytm 2020, as

our talented scientists. described in the following pages. C T FROM THE CHAIRMAN

Over the last two decades, our ability critical information for the diagnosis, In our previous book, we to interrogate the human genome prognosis and treatment of disease. introduced the concept of Precision has radically transformed . In addition to determining if an Ophthalmology™: using each Sequencing the genome went from individual is at risk for developing a individual’s own genetic profile a billion-dollar project that required certain disease, we will also be able to tailor a course of treatment A more than ten years of exhaustive to advise them about the risk that specifically designed for him or effort, to a routine task that is their children or other loved ones will her. Columbia’s Applied Genetics regularly completed overnight in our develop it as well. In the related and Initiative in Ophthalmology is a G labs for a few hundred dollars. emerging field of pharmacogenetics, global leader and is making Precision With that achievement has we no longer have to deliver drugs Ophthalmology™ a reality for our Department Milestones 06 come virtually limitless opportunities by trial and error. Instead, we are patients today. In these pages, we’ll to take what we know about the increasingly able to use genetic show you how. Genetics Primer 1 4 genetics of disease and risk, and information to predict a person’s the possibility of treating faulty response to available drug treatment genes, and deliver that knowledge to options and select the that is Foundational Biology 1 6 patients in a way that makes a most likely to work for them. CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACACTCAG CAGCATCATTCATTTCGGTTTACACGATCCAGAGTGCGGTAACCTTAACCT05AGC Vision Science Today 24 meaningful difference in their lives. There are also evolving This new field of ophthalmology, treatments that are directed and in fact all of medicine, is known specifically at particular genetically The Inheritance Question 32 as Applied Genetics. Precision determined diseases. Many of the Ophthalmology™ 2020 explores the most significant advances in gene Genetic Testing & 38 promise of this growing field, and the therapy for the treatment of disease work that is being done within the have occurred in ophthalmology, new Applied Genetics Initiative at the including the first FDA-approved Disease-Specific Applications 46 Columbia University Department of for the treatment of any G.A. (Jack) Cioffi, MD Ophthalmology, to make the most of disease. Edward S. Harkness Professor Gene Discovery 58 those possibilities. So, while we can expect further Jean and Richard Deems Professor We do not need to wait for great leaps forward in gene therapy Chair, Department of Ophthalmology full-fledged gene-based “cures” for and gene in the very near Clinical Trials 64 diseases to leverage our genetic future, we already have the ability, knowledge in ways that can transform today, to leverage the genome for The Future 70 people’s lives. Understanding an diagnosing, counseling and treating individual’s genotype, and how individuals with genetic . that genetic code interacts with Applied Genetics informs every step environmental factors to produce the of the process: determining who observable traits or characteristics should be tested, how testing can be that we call phenotype, already yields best utilized, and evaluation of the personal and family implications of TC being tested. DEPARTMENT MILESTONES

1935-36 Discovery of hyaluronic acid by Dr. Karl Meyer. 1933 The Department moves Phillips Thygeson, 1866 Cornelius into the Edward S. Harkness Eye MD, OphD, describes R. Agnew, MD, Institute on 165th Street. the microbiologic establishes an transmission of ophthalmology . clinic at the 1903 Arnold H. College of Knapp, MD, son of Physicians and Herman, appointed Surgeons. professor of 1938 Dr. Castroviejo ophthalmology at 1911 Edmund B. urges people to P&S and becomes Wilson, PhD, maps will their eyes to the third clinic color blindness onto science, leading to director. the X chromosome. the development of today’s eye banks.

1931 Edward S. Harkness pledges money to build a separate Eye Institute 1943 Raymond 1869 Herman at the new medical L. Pfeiffer, MD, J. Knapp, MD, center. is the first to establishes the New delineate the York Ophthalmic landmarks of the and Aural Institute, ocular orbit on which later becomes plain x-rays. the Herman Knapp Memorial Hospital.

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1867 Dr. Agnew is appointed the first professor of ophthalmology at P&S, marking the 1888 Dr. official beginning Herman Knapp 1939 Dr. Thygeson of the program. is appointed 1933 Ramon becomes the fourth professor of 1911 Herman Knapp Castroviejo, MD, clinic director, ophthalmology at Memorial Eye Hospital, performs the first serving until 1945. founded by Arnold Knapp, P&S, and becomes 1928 Presbyterian Hospital corneal transplant on opens at 10th Avenue and the second clinic moves to 168th Street, and a human. 57th Street, two blocks 1940-41 New director. the Vanderbilt Clinic—the from P&S. The Eye staff at methods for clinical care unit of P&S, with P&S hold appointments at quantitative analysis its Ophthalmology service— the new hospital. of intracellular sugars moves uptown with it. John M. are developed by Wheeler, MD, DSc, becomes the Dr. Zacharias Dische. first chair of the Department of The Knapp Hospital Ophthalmology. closes, and the Knapp Memorial Library of Physiological Optics 1936 The Muscle Clinic becomes the opens. Eye Institute’s first clinic.

1st Clinic Director 2nd Clinic Director 3rd Clinic Director 1st Department Chair CORNELIUS R. AGNEW, MD HERMAN J. KNAPP, MD ARNOLD H. KNAPP, MD JOHN M. WHEELER, MD, DSC 1867-1888 1888-1902 1903-1928 1928-1939 DEPARTMENT MILESTONES

1966 Saiichi Mishima, MD, 1962 First develops a system keratoprosthesis, for preserving developed by Hernando corneas until Cardona, MD, is transplantation. presented to the 19th 1947 First International Congress of retinoblastoma, Ophthalmology. pediatric, and adult ocular tumor clinics are established by Dr. Algernon B. Reese. 1958 World’s 1968 David Maurice, MD, and first clinic Dr. Donn are first to use confocal is established by microscopy to detect new Charles J. Campbell, 1956 George Merriam Jr., structural features of the eye. MD, PhD. MD, with Elizabeth Focht, American Optical Company MD, of NYU, establishes releases its monocular indirect a relationship between ophthalmoscope, developed in formation and 1961 Frank part by Dr. Campbell. radiation. This leads to the Carroll, MD, a 1964 First development of standards leader in research basic and on diseases of of ocular radiation safety clinical corneal 1969 D. Jackson Willis the optic nerve, 1948 still in use today. research center Coleman, MD, Knighton, MD, establishes an established develops the first establishes a Optic Nerve Clinic. by Drs. Gerard commercially Clinic DeVoe and available hand- on the newly Anthony Donn. operated ultrasound remodeled fifth B-scan system floor of the Eye for ophthalmic Institute. evaluation.

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1969 Dr. Phillip Knapp describes a 1961 Dr. Campbell muscle transposition 1948 The is first to use the procedure for pupillography ruby laser in humans, paralytic strabismus laboratory is 1955 American Optical working with Rittler that becomes established by releases the AO HRR color and Charles Koester, known as the Otto Lowenstein, vision test, developed MD. Fight for Sight “Knapp procedure” MD, PhD, a by LeGrand Hardy, MD, Children’s Eye Clinic and remains in pioneer in the director of the Knapp added to the Eye common use to this quantitative Memorial Physiological 1957 Irene Institute, headed by day. measurement of Optics Laboratories, and M. Loewenfeld, PhD, 1962 John W. 1966 Max Phillip Knapp, MD. pupil function. Catherine Rittler, working and Dr. Lowenstein Espy, MD, creates Forbes, MD, with Gertrude Rand, PhD, build an “electronic the Eye Institute’s describes of Johns Hopkins. pupillograph” that Contact Lens indentation incorporates infrared Clinic, which he gonioscopy in technology. It is directs for 25 closed-angle the first device to years. glaucoma. accurately measure and analyze the diameter of the pupils.

1968 First argon laser is 1965 Black Medical used to treat human disease Research Building by Francis L’Esperance Jr., is completed. From MD. Harold Spalter, MD, is 1965 to 1969, the 15th among the first to publish floor is heavily utilized on the use of lasers for the for ophthalmology treatment of diabetic macular laboratories. edema and central serous 2nd Department Chair 3rd Department Chair retinopathy. JOHN H. DUNNINGTON, MD A. GERALD DEVOE, MD 1946-1959 1959-1974 DEPARTMENT MILESTONES

1973 Using the ultrasound he developed, Dr. Coleman demonstrates that operating 1983 Dr. Trokel at an earlier stage in ocular publishes a major trauma can vastly improve paper introducing the patient’s prognosis for the idea of using recovery. the laser to reshape or sculpt the 1987 Stephen 1998 cornea. Dr. Trokel Trokel performs the R. Duff and Carol 1994 Peter and Dr. L’Esperance first human excimer Kurland establish Gouras, MD, PhD, (pictured) patent laser surgery for the Anne S. Cohen performs the first the excimer laser for vision correction. Professor of Pediatric vision correction human retinal cell . Ophthalmology. 2000 John 2005 The Bernard transplants. Flynn, MD, joins and Shirlee Brown the Department as Glaucoma Research the first Anne S. Laboratory opens. Cohen Professor of Pediatric 1997 Ophthalmology. Latanoprost (Xalatan™) for the treatment 1980 Stephen of glaucoma, Trokel, MD, developed by publishes findings Endre Balasz, MD, Dr. Laszlo Bito, on techniques 1983 Malcolm P. Aldrich Research is marketed for submillimeter Professor and Director of worldwide. resolution CT Research in the department, scanning of orbital develops Healon, a hyaluronic diseases. acid polymer that transforms cataract and corneal surgery.

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1972 Abraham Spector, PhD, publishes research on protein aggregation and 1998 NewYork-Presbyterian cataract formation. is formed, becoming His laboratory will the Ophthalmology become one of the Department’s partner and world’s leading the number-one hospital cataract research system in New York City. 2004 Opening of the Louis V. laboratories. Gerstner Jr. Clinical Research Center in Vision, which houses 1986 Basil V. Worgul, PhD, who the Russell Berrie Diabetic directs Columbia’s Eye Radiation Retinopathy Research Unit and and Environmental Research 1996 The FDA the Starr Foundation Retina Lab, is named American director approves the use of Research Unit. of the Ukrainian/American perfluorocarbons Chernobyl Ocular Study. 1993 Dr. Trokel for retinal surgery describes orbital fat through the work of removal for orbital Dr. Stanley Chang. 2005 Janet decompression. Sparrow, PhD, 1998 The Flanzer Eye named Anthony Center opens on the Donn Professor Harkness Eye Institute’s of Ophthalmic 1980 Charles Koester, MD, first floor, and the Science. develops the first wide-field Low Vision Clinic is specular microscope, which established under Dean proves to be invaluable Hart, OD. for studying the corneal endothelium.

4th Department Chair 5th Department Chair 6th Department Chair CHARLES J. CAMPBELL, MD, PHD ANTHONY DONN, MD STANLEY CHANG, MD 1974-1987 1987-1996 1996-2012 DEPARTMENT MILESTONES

2016 Basic 2013 Donald ourse in O Science Course in C p e h Hood, PhD, c t Ophthalmology n h ie a elucidates l c m (BSCO) S

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years of training B relationship of 2017 Irene Maumenee, MD, Petrukhin, PhD, residents in the 2011 Vision glaucomatous 75 joins the department and develops tinlarebant, a YEARS fundamentals of Neuroscientist, damage to the Est. 1941 receives the Laureate award new drug for Stargardt vision science. Carol Mason, PhD, macula. from the American Academy disease and dry AMD Steven is elected to 2013 of Ophthalmology for her that successfully Brooks, MD, joins the Institute of lifelong contribution in completes testing in the department Medicine. ophthalmic genetics. Phase I clinical trials. as Anne S. Cohen Professor of Ophthalmology to direct the pediatric 2019 David and ophthalmology Victoria Foley establish division. the Foley Retina 2017 Brian Research Fund and the 2006 Rando Marr, MD, Allikmets, PhD, Foley Clinical Retinal is named Fellowship Endowment. and the AMD 2015 Jeffrey professor of Study Group 2014 The Robert Liebmann, MD, joins ophthalmology, Stephen discover factors 2012 Burch Family Eye Center the department as leading a Tsang, MD, PhD, is H and B, genes opens at the Lighthouse Vice-Chair, Glaucoma relaunch of named László Z. contributing Guild International on Division Director and the Division Bitó Professor of to age-related the Upper West Side of the Shirlee and Bernard of Ocular Ophthalmology. macular Manhattan. The Stephen Brown Professor of . degeneration. Ross Pediatric Eye Center Ophthalmology opens at Morgan Stanley Children’s Hospital.

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2019 Simon John, PhD, a Howard 2012 The Jean Hughes investigator in and Richard Deems glaucoma and other Professorship of neurodegenerative Ophthalmology & diseases, is appointed Endowment Fund is Robert L. Burch III 2005 Mr. and Mrs. Herbert established, leading to the 2016 Ronald Silverman, Professor of Ophthalmic Irving endow the new recruitment of G.A. (Jack) 2014 Xin Zhang, PhD, PhD, develops an advanced Science. Florence and Herbert Irving Cioffi, MD, as the 7th is named the Jules and ultrasound technology to Translational Vision Research Department Chair. Doris Stein Research measure ocular blood flow. Laboratory. to Prevent Blindness Associate Professor. 2017 Jonas 2015 Tongalp Tezel, MD, Children’s Vision joins the department as Care program opens Chang Family Professor 2012 Leejee H. to provide advanced of Ophthalmology to Suh, MD, is named care to children with lead the retina service. Miranda Wong Tang sight-threatening Associate Professor of disorders. Ophthalmology and Chief of the Cornea 2019 Applied Service. 2017 Royce Chen, MD Genetics at Columbia 2010 The Columbia Laser and Lora Glass, MD are Ophthalmology is Vision Correction Center and appointed Residency 2015 Jean and launched. the Gloria and Louis Flanzer Program and Associate Kent Sheng Vision Care Center open. Residency Program establish a Directors. glaucoma fellowship endowment.

6th Department Chair 7th Department Chair STANLEY CHANG, MD G.A. (JACK) CIOFFI, MD 1996-2012 2012- GENETICS PRIMER

A T C G

DNA GENE CHROMOSOME CELL

NUCLEUS

GCATCATT14ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA15CTCAGC

The blueprint of all human A gene is a portion of DNA that The four bases—adenine, thymine, Genetic counselors help individuals characteristics—everything that contains instructions to build a cytosine and guanine (A, T, C and and families uncover inheritance makes us who we are—is encoded unique gene product, usually a G)—are the nucleotides found in patterns of a specific genetic within DNA (deoxyribonucleic protein or enzyme, that performs a DNA. Through the technique of diseases within a family, which acid). DNA is the basic unit of function in a specific tissue. DNA sequencing, first developed provides important clues for heredity passed from generation to by Frederick Sanger, scientists diagnosis. This form of diagnosis is Genetic diseases occur when generation. can determine the exact order of called Precision Medicine because there is a defect in the way a gene nucleotides in an organism’s genes. it applies genetic information Each one of our cells contains is encoded, resulting in a faulty Knowing this order is the first step directly to patient care and allows the DNA that controls every gene product that is absent or in our efforts to map the DNA for the development of targeted aspect of cellular health and dysfunctional. sequences of all organisms and and individualized treatments. therefore our overall health. DNA, The genome is the collection of thereby connect gene sequence a complex molecule, is contained Gene therapy refers to the delivery all genetic information on all of with gene function. within cellular structures called of a new, functional gene to replace our chromosomes, and genomics chromosomes. Diagnostic sequencing is the a nonfunctional inherited gene. This is the study of the genome to analysis of DNA from a individual new type of therapy relies heavily identify causes of disease and their person and his or her family to on discoveries in basic research prevalence in the population. determine which gene is causing a laboratories. disease. “Foundational biology serves as the basis for the acquisition of new knowledge and the catalyst for future discoveries and avenues of new research.” —Simon John, PhD FOUNDATIONAL FIGURE 1.a FIGURE 1.b BIOLOGY

A The early embryonic eye is defined Causative Genes The recent revolution in genetic make precise molecular diagnoses by overlapping expression of in Ocular Disease studies, based on “next-generation and plan individualized therapy for regulatory genes. At the early stage sequencing” technology, has allowed hundreds of inherited eye diseases. of development, all the ocular scientists to obtain detailed genetic Emerging technologies also allow us progenitor cells express Pax6 data on entire genomes in hundreds to study individual genetic variants G (blue), without which the entire eye of thousands of individuals. With this in disease models and, eventually, development program is aborted. information, we can not only discover correct genetic errors in patients. Pax6 cooperate with additional disease-causing mutations in single At Columbia Ophthalmology, we transcription factors such as Sox2 genes but also identify the genetic are applying state-of-the-art genetic to precisely specify the different variation in an individual associated methods to diagnose and treat parts of the eye. They also interact with all observed phenotypes, from specific eye diseases. By sequencing with signal Regulated Transcription benign individual variations to simple genomes and their protein-coding Factor such as Lef1 (red), a and complex diseases. “Phenotype” parts, exomes, in thousands of downstream effector of Wnt is the term used to describe the patients with eye diseases, we signaling. Together, these factors observable characteristics of have been able to identify genetic regulate the intricate and precise an individual resulting from the variations causing single-gene development of the eye. interaction between their genes and diseases, such as Stargardt disease Xin Zhang, PhD the environment. As a result, we can and , and

GCATCATT18ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA19CTCAGC

Development of the Eye Just as the tectonic movement of control gene expression), which Localization of genes complex, multifactorial diseases the earth created the continents, the translate the developmental program and proteins involved such as age-related macular immense complexity and structural into changes in gene expression, in retinal diseases is degeneration and myopia. We have diversity of the eye arises from the dictating the identity and function shown in the retinal introduced these variants in mouse collision of two tissues: the optic cup of each ocular tissue. Through the pigment epithelium and cell-based models, enabling and the lens vesicle. The optic cup combined activity of signaling (RPE), rod and cone the development of precisely traces its origin to the central nervous pathways and transcription factors, outer and inner defined, genetics-based therapeutic system, and the lens vesicle shares its vast number of ocular cells are segments, in the approaches based on small pedigree with the skin. As the pro- specified to perform the necessary nucleus and synaptic molecules, stem cells, gene therapy neural optic cup wraps around the function of the eye. body. Genetic testing and gene correction therapy. We epidermal-like lens vesicle, these two identifies mutations call this Precision Ophthalmology™: tissues send signals back and forth in these genes, which comprehensive, interactive patient by releasing small molecules that can cause a spectrum of care, integrating state-of-the art activate intracellular pathways. These retinal diseases. clinical characterization and an cross talks are crucial for guiding Rando Allikmets, PhD unprecedented depth of genetic the development of the optic vesicle analyses, to achieve personalized

Overleaf: In a mouse into the light-sensing retina and the treatment of eye diseases. model of retinopathy of lens vesicle into the light-focusing prematurity, new blood lens, while maintaining the perfect vessels (red) grow to symmetry and proportions of the occupy the surface of the eye structures. Helping to interpret retina overlaid with the these signals within the cells are neural fibers (blue) and astrocytes (red). transcription factors (proteins that Xin Zhang, PhD TC FOUNDATIONAL BIOLOGY FIGURE 1.c FIGURE 1.d BIOLOGY

Use of Models in Ocular Genetic Research

Stem-cell-based disease models, sometimes referred to as a “disease in a dish,” can recapitulate key aspects of ocular and other health disorders. This is particularly true if the induced pluripotent stem (ipS) cells are specific to a patient and the patient’s cells are grown in the laboratory. Combining ipS technology with recent advances in gene editing and in the construction of three-dimensional cell culture systems further increases the value of Expression changes in the mouse retina associated with different levels of activity of the retina-specific nuclear bioengineered models of eye disease. receptor NR2E3. Disease mutations in the photoreceptor-specific nuclear receptor NR2E3 are responsible for These cell culture systems can be the enhanced S-cone phenotype in humans. Transcriptome analysis reveals a photoreceptor survival signature clinically relevant and can help to associated with certain levels of NR2E3 activity. Small-molecule NR2E3 modulators may promote photoreceptor bridge the gap between survival in patients with degenerating retina. Konstantin Petrukhin, PhD

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A stylized image of fundus the clinical presentation of ocular Using Genes to To discover gene-related drug pathways and potential drug targets autofluorescence in the Abca4- disorders and an understanding of Create Therapies targets that can be modulated with allows pharmaceutical researchers to /- mouse, a model of recessive the genetic cellular and molecular therapeutic interventions, we must develop new therapies for currently Stargardt disease. Fundus mechanisms that cause tissues to first define the genetic mechanisms untreatable ophthalmic disorders. autofluorescence originates in malfunction. Cell culture systems also responsible for disease. In recent Pharmacology and medicinal bisretinoid molecules that accumulate provide a platform for testing novel years, scientists at Columbia chemistry, combined with the power in retinal pigment epithelium. This therapeutics and for serving as the Ophthalmology have made significant of current genomic technologies, will autofluorescence is amplified in essence of regenerative medicine. progress toward understanding play an essential role in developing patients presenting with ABCA4- Breakthroughs in understanding the causes of relatively rare, single- novel drug treatments in years to disease. This disease feature is retinal disease have also relied gene ophthalmic disorders such as come. replicated in the mouse model. The heavily on animal models, beginning Stargardt disease, Best vitelliform spots (white) are also a feature of the with the fruit fly and zebrafish. The macular dystrophy and juvenile disease in mice. importance of these models lies in glaucoma. By applying modern Janet Sparrow, PhD their ability to aid in the identification genomic technologies, we also have of causative genes and gene been able to identify predisposing products. They also assist in unveiling genetic factors that contribute to disease mechanisms. Preclinical more common ophthalmic diseases testing in animal models is essential such as age-related macular to the discovery of novel disease degeneration, myopia and primary mechanisms and to the advancement open-angle glaucoma. The explosion of treatments for humans. of genetic information about FOUNDATIONAL BIOLOGY FIGURE 1.e FIGURE 1.f BIOLOGY

near work lag of accommodation negative optical defocus increased eye growth myopia

visual genes genes genes environment environment + genes

emmetropia environment genes 42% (near work/reading) 70% hyperopia 30% 10% myopia 48%

This figure shows a chain of events leading to the development of myopia. The main environmental factor causing myopia is near work, such as reading, which is associated with the accommodative effort required to focus the image on the retina. This results in negative optical defocus, which stimulates excessive eye growth and ultimately leads to myopia (top panel). The contribution of environmental factors in the development of myopia has been estimated at 30%, while the contribution of genetic factors has been estimated to be close to 70%. Andrei Tkatchenko, MD, PhD

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Neurodegeneration Many of the cells within the eye are combined with sustained release Gene-Environmental Myopia, better known as near- the development and progression nerve cells, also known as neurons. of neurotoxic mediators, create a Interactions sightedness, is a complex genetic of myopia in humans. Many of Improved understanding Degeneration of neurons, termed vicious cycle that promotes further disease. It results from the interaction these genes were found to be of cellular and “,” is a feature injury to neurons within different between environmental and genetic involved in the gene-environment molecular mechanisms of many ocular diseases, including compartments from the retina to factors, which shape the geometry of interactions underlying refractive of neuroinflammation glaucoma, age-related macular the brain. Therapeutic modulation of the eye and determine its refractive eye development. One such gene, will allow us to test degeneration, , neuroinflammation therefore offers state and need for eyeglasses. The APLP2, was found to be involved immunomodulation as a optic neuropathies and some a promising treatment strategy for leading environmental factor causing in gene-environment interaction neuroprotective treatment inherited disorders of the retina. widespread neuroprotection. Recent myopia is near work (looking at underlying the development of strategy for glaucomatous Through studies of human donor studies have revealed a promising close objects for extended periods myopia in children. Children who carry neurodegeneration. tissues and experimental models, target for this treatment approach: of time); however, several other a “myopic” version of the APLP2 gene Gülgün Tezel, MD departmental researchers are NF-KB, the key transcriptional environmental factors, such as light are five times more likely to develop seeking to uncover new therapeutic activator of inflammatory intensity, day-night light cycles, myopia if they engage in prolonged approaches to protect, rescue mediators. By profiling cell-type- and exposure to outdoor activities, close work, thus confirming an and regenerate neurons in these specific proteomic alterations and have also been implicated. Although important role of gene-environment blinding conditions. Research in this conducting functional testing of environmental factors play a very interaction in myopia development. field seeks to pinpoint molecular outcome molecules through cell- important role in its development, mechanisms of neurodegeneration type-targeting transgenic strategies, genetic factors account for about and identify novel neuroprotective it is possible to inhibit NF-KB to 60-80% of the propensity for myopia. treatments. A growing body of provide neuroprotection through At Columbia Ophthalmology, it was research suggests that chronic immunomodulation in glaucoma and recently discovered that as many tissue stress, neuronal injury, glial possibly in other ocular diseases. as 3,500 retinal genes and over 80 and systemic immune responses, retinal pathways are involved in “The field of vision research is benefitting from advances in non-invasive ocular imaging, DNA sequencing technology, animal modeling, stem cell generation and gene therapy.” — Carol Mason, PhD VISION SCIENCE TODAY FIGURE 2.a FIGURE 2.b

High-throughput sequencing: Each of the nucleotides (A,T,C,G) A is fluorescently labeled with a different color, allowing their specific identification. The DNA is first fragmented into smaller pieces—known as library G preparation. The specific fragments are fixed to a glass substrate in high-density clusters. During sequencing, the fragments in each cluster are copied by synthesizing new DNA strands. As specific bases are added to the DNA strands, the clusters are repeatedly imaged with a laser, allowing determination of the unique DNA sequence in each cluster based on the color of the Chapter 2: Techniques for Oral Microbiology.” Atlas of Oral Microbiology: from Healthy sequentially attached fluorescent Microflora to Disease, by Xuedong Zhou and Yuqing Li, Academic Press, an Imprint of Elsevier, 2015, pp. 15–40. Figure 2.39: Illumina Sequencing tags. Simon John, PhD GCATCATT26ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA27CTCAGC

Building Genetic Models Animal models are vital for CRISPR-Cas9 gene editing Phenotyping When we talk about an individual’s “Phenotype” is the term used for understanding the molecular technology allows us to target the phenotype, we are referring to the observable features (such as eye processes underlying eye diseases mammalian genome more directly sum total of their observable traits— color, eyelid configuration and and for testing potential therapies and rapidly, providing a versatile everything from hair color and eye eyebrow size) that results from the before human clinical trials. Due means to generate next-generation color to manifestations of disease. A combined effects of environmental to similarities in anatomy and models in mice and other species. person’s phenotype is the product and genetic factors. physiology, the mouse is a widely These advances have opened a of the interaction of their genotype G.A. (Jack) Cioffi, MD used animal model for studying the golden era of genetics for the (their total genetic inheritance) human eye. In one approach, mouse study of complex ocular diseases, with the environment. In Precision genes are systematically altered fueling research to identify novel OphthalmologyTM, phenotyping to pinpoint their exact functions in mechanisms and treatments. Some describes the effort made to observe development and disease progression. of our ongoing studies are focused the features of a healthy eye or the At Columbia Ophthalmology, we on the development of key ocular characteristic changes due to disease. utilize sophisticated methods tissues (including Schlemm’s canal, Phenotyping is important as it can including conditional disruptions of ciliary body, optic nerve and retina) direct our efforts to discover new genes in tissue- and stage-specific as well as a variety of retinal diseases, genes associated with eye disease, and manners and point mutations such as Stargardt disease and age- aids in gene discovery. For the patient (changing a single base pair in the related . We in the ’s office, accurate DNA sequence) to alter proteins. A are also modeling genes associated phenotyping helps us establish a complementary approach utilizes with glaucoma in order to generate connection between eye disease and data from the general population to improved models and to assess an underlying gene defect, and may identify unknown genes involved in and metabolism- link the gene defect to a specific, development and disease. protecting treatments. individualized treatment for the patient and affected family members. VISION SCIENCE TODAY FIGURE 2.c FIGURE 2.d

Mode image of treated choroidal malignant melanoma located GLAUCOMA inferiorly in the right eye of a 47-year-old woman. Although the tumor was treated 17 years ago and shows no growth in recent exams, color-flow Doppler (insert) derived from plane-wave ultrasound techniques developed at Columbia demonstrate CONTROL blood flow, primarily in the anterior aspects of the lesion. Visualization and measurement of blood flow in ocular tumors may provide a novel means for assessing metastatic potential and responsiveness to treatment. A C D. Jackson Coleman, MD

GCATCATT28ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA29CTCAGC

Biomarkers of Disease Biomarkers are surrogate Multicolor flow cytometry- Ultrasonic Imaging Intraocular tumors are often highly measurements that can be used based analysis of T lymphocyte of Phenotype pigmented, which severely limits the to detect or monitor a condition subset distribution shows usefulness of optical methods such or disease. Molecular biomarkers a decreased percentage of as optical coherence tomography in can improve clinical prediction, T-regulatory cells (CD4+/ their capacity to provide diagnostic early diagnosis and monitoring of CD25+/FoxP3+ fractions of information. Because ultrasound is diseases. This can be facilitated by isolated T lymphocytes) in less subject to scattering and absorp- the study of proteins (proteomics blood samples of patients with tion by pigment than is light, it has and immunoproteomics) to identify glaucoma compared to normal long been of crucial importance in candidate molecules for validation in controls. Gülgün Tezel, MD assessment of tumor thickness pre- the clinical testing of ocular diseases. and post-treatment by brachyther- Since many eye diseases are complex apy. Conventional B-scans, however, and variable among patients, analysis only provide information on tumor of a set of biomarkers—including position and thickness. Recently some specific molecules, oxidative developed Doppler techniques can stress-related candidates and T assess both tumor anatomy and lymphocyte profiling being evaluated blood flow within the tumor and in in our laboratories—may allow us to feeder vessels. develop a blood testing panel that can improve our clinical prediction of disease and facilitate follow-up of treatment responses. A T VISION SCIENCE TODAY FIGURE 2.e FIGURE 2.f

Optical coherence tomography (OCT) and fundus autofluorescence (FAF) are noninvasive imaging methods that play a key role in the diagnosis and management of inherited retinal

10 U This photomicrograph degenerations (IRDs). The results demonstrates color-flow Doppler contribute to our understanding of images of a pre-term neonate the pathophysiology of IRDs and to

12 obtained using plane-wave correlations between genotype and ultrasound techniques developed in phenotype (the set of observable our labs. The project is supported characteristics resulting from

14 by a Jonas grant and aims to find interaction between genotype markers representing retinopathy and environment). Using OCT, we of prematurity risk factors. The can evaluate the integrity of the

16 images depict vessels in the region outer and inner retinal layers both Flow Direction Flow of the optic nerve: red colors depict qualitatively and quantitatively. For arteries, and blue depicts veins. The example, in patients with retinitis

18 central retinal artery and vein are pigmentosa, we can use OCT to seen, as is the short posterior ciliary visualize damage or disruption of artery, retina and choroid. Imaging for the photoreceptor layers and to

mm D Ronald Silverman, PhD Diagnosis observe any loss of integrity of mm 2 4 6 8 10 12 the external limiting membrane GCATCATT30ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA31CTCAGC

Imaging as a Biomarker In the last decade, a novel approach prematurity are now underway. The (ELM) and ellipsoid zone (EZ) band. to Doppler imaging called “plane- application of plane-wave ultra- Quantitative assessments of EZ wave” ultrasound was developed. sound Doppler offers an exciting width and outer segment (OS) layer With this technique, unfocused ultra- new avenue for functional and struc- thickness can be used as markers sound is transmitted and focusing is tural imaging of the eye in health of disease progression. We can also achieved by computer post-process- and disease. generate en-face OCT images of the ing. Plane-wave enables acquisition retinal layers at any specified depth, of many thousands of B-scans per providing morphologic information second, which facilitates identifi- that we can then compare to

cation of tissue motions, including OCT and FAF images for a patient changes observed on FAF images. flowing blood. Columbia researchers with retinitis pigmentosa.. Novel techniques for wide-field and in the Silverman Lab have developed A. Image depicting a cross section of swept-source (SS) OCTs and wide- this technology for imaging the eye. macula and optic nerve anatomy. field fundus autofluorescence now Not only does it provide high-reso- B. En-face image with EZ band as permit us to evaluate regions outside lution color-flow images but it does the reference showing the boundary the central retina—regions that are so at intensities compliant with strict of the intact EZ band. affected in IRDs such as Stargardt regulatory standards. Clinical studies C. Averaged B-scan. disease and retinitis pigmentosa. of ocular blood flow in glaucoma, D. FAF image showing ring of hyper These techniques will make it preeclampsia and in low-birthweight autofluorescence. possible to study cohorts of patients neonates at risk for retinopathy of Vivienne Greenstein, PhD with specific gene mutations, identifying relationships among measures and documenting disease CG progression. “Hereditary risk assessment necessitates genetic testing to allow families to understand their familial risk and answer the question: Will my children get my disease?” — Irene Maumenee, MD THE INHERITANCE QUESTION FIGURE 3.a FIGURE 3.b

1

2

A 3 G Sequencing is the basis of C modern genetic testing, Each of the nucleotides (A,T,C,G) is 4 T fluorescently labeled with a different color. A representation of fluorescent signal from a single cluster is on the left. Simon John, PhD GCATCATT34ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA35CTCAGC

Will My Children Inherit The interplay of a person’s genetic by gender, without other copies? Genetic Testing in the Each of us knows that many diseases manipulate the genome has emerged. My Disease? information with environmental Is there a role for environment or Modern Society have some component of heritability, This empowers each of us to better factors is often a major force in other factors to lessen or exacerbate whether it be within our own understand our own disease risks, disease development. Alternatively, the impact of the mutation? The families or others. The fundamental tendency for familial inheritance, a person’s genes can be the primary genome of each individual is unique underpinning of modern genetics prognosis and potential therapies. driving factor in the development of a and varies from person to person. began with the discovery of DNA. disease, regardless of environmental This complexity and diversity among In the past two decades, our ability exposures. A mutation of a single individuals with and without disease to analyze the human genome has gene can cause disease at a discrete is why genetic testing and counseling swiftly become routine, much more level (just in one tissue or organ, such is critical. widely available and less costly. This as the eye) or throughout the body, has led to its increasingly common depending on how developmentally use in daily medical practice in critical the mutated gene is. Each such diverse fields as maternal- of us is supplied with two sets of fetal medicine, oncology, genes from our parents (one from and ophthalmology. Commercially Mom and one from Dad). If you have available gene testing kits are a disease that results from a genetic increasingly common but do not mutation, your children have a risk yet offer the precise diagnostic of inheriting that disease, but the capabilities found in the scientific and level of risk is dependent on several medical communities. Our existing factors. Are both copies of the gene database of genetically determined required in order to be healthy? Is the ocular diseases is rapidly expanding mutation in a location that is defined while at the same time our ability to THE INHERITANCE QUESTION FIGURE 3.c FIGURE 3.d AG

Genetic counselors educate patients about their genetic testing results. This allows patients to make informed decisions about their medical management. Megan Soucy, MS, CGC GCATCATT36ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA37CTCAGC

A Family’s Perspective Applied ophthalmic genetics way for families and children with Genetic Counseling “Genetic counselors are professionals no biological relatives available, but integrates many facets of eye care sight-threatening conditions such as who have specialized education in family member testing is needed to Celebrating the launch and vision research and offers us congenital cataract and glaucoma genetics and counseling to provide interpret results. Genetic counseling of Jonas Children’s the potential to reach new goals to get the advanced testing and personalized help that patients may addresses these concerns while guiding Vision Care with the need as they make decisions about their individuals through the testing process that previously would have been treatment they need to save their Jonas family, made genetic health.” —The National Society and interpretation of results. While considered impossible. These vision. Applied Genetics also allows possible by the of Genetic Counselors (2019) genetic counseling can be performed include novel discoveries, innovative children with syndromes that can generosity of Barbara by a physician, oftentimes the use of therapies and the delivery of state- affect multiple organs and tissues, Genetic test results affect families—not and Donald Jonas. a genetic counselor is beneficial. The of-the-art, personalized care for such as Marfan syndrome or Usher just individuals. In order to accurately G.A. (Jack) Cioffi, MD genetic counseling process allows interpret the results of genetic tests, each patient. We can only achieve syndrome, to be evaluated and for more time to devote to these we often need to include information these lofty aims through partnerships treated for vision-threatening conversations, allowing individuals from other family members. Individuals between dedicated medical teams complications, as well as helping to undergoing testing to feel confident undergoing genetic testing can feel on the one hand, and philanthropists guide genetic testing and referrals to and empowered by their genetic a myriad of emotions, such as guilt, with a commitment to curing disease other pediatric specialties. Applied health information. At Columbia shame, anxiety and relief—feelings on the other. The Jonas Initiative, Genetics at Columbia Ophthalmology, Ophthalmology, we have genetic that are made even more complex by created with a generous gift from and its partnership with philanthropy, counselors who have been specifically family dynamics. Family secrets such Jonas Philanthropies, is an example of has virtually limitless promise to trained in ophthalmic diseases to assist as nonpaternity can be discovered; such a partnership. The funding from transform the lives of children and patients and families. individuals might need to communicate this gift has allowed the expansion families with complex medical with estranged family members; of pediatric eye care and research, conditions. and sometimes an individual has as well as a substantial investment in Applied Genetics, at Columbia Ophthalmology. It has paved the TC “Understanding the genetic basis of a disease will aid in the hunt for new therapies and allow clinicians to select specific therapies for specific patients.” — Janet Sparrow, PhD CLINICAL GENETIC FIGURE 4.a FIGURE 4.b QQ Plot: Observed vs. expected p-values. Lambda = 1.03623 TESTING & THERAPIES 14 2.5 percentile of expected p-values disease phenotype, or a similar one— 97.5 percentile of expected p-values but managing the disease may differ Quantile-quantile (QQ) plot based on which genes are involved. 12 for exome-wide gene-based collapsing analysis under A When a genetically linked disease the dominant genetic model occurs in a family, the risk of that 10 in a cohort of patients who disease recurring in other family clinically presented with members can vary from zero to 50%. Stargardt disease but had When DNA analysis finds a previously 8 no mutations in ABCA4. The T identified genetic mutation that is analysis identified the top compatible with an observed disease three genes, PRPH2, PROM1 6 phenotype, our counseling changes and CRX, that reached from an estimated risk of recurrence Observed -log10(p) Observed genome-wide significance. to a confirmed probability, or even These genes are the primary 4 100% certainty. Understanding candidates for causality in the genetic underpinnings of a macular diseases mimicking particular condition allows us to 2 Stargardt, allowing for precise provide diagnosis and counseling genetic diagnosis. at many stages: prenatal diagnosis, David Goldstein, PhD preimplantation diagnosis, pre- 0 Rando Allikmets, PhD symptomatic diagnosis and early 0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 management. We can also confirm Expected -log10(p)

GCATCATT40ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA41CTCAGC

Why We Do Genetics Testing We conduct genetic testing on that a person is healthy and will Rare Disease Advances in next-generation Collaborators from IGM and individual patients for three main not develop a particular disease. Identification sequencing have revolutionized both Ophthalmology seek to identify reasons: to improve understanding of Counseling should be provided by gene discovery and the diagnostic individuals with specific phenotypes, A young blind Pingelapese a patient’s disease, to understand the certified genetic counselors, medical analysis of patients with rare such as macular telangiectasia, age- man sitting in his boat risk of disease recurrence in a family geneticists or, ideally, double- diseases. Our Institute for Genomic related macular degeneration and but unable to identify the and to foster patients’ participation board-certified genetic ophthalmic Medicine (IGM), directed by Dr. David Stargardt-like retinal dystrophies, low-lying “Island of the in their own care and search for geneticists. Goldstein, has been instrumental in to participate in research aimed at Colorblind” in the distance. knowledge. using these advances and related identifying new genes and enhancing The gene mutation that Patients will benefit most from the statistic genetic approaches to precision diagnosis. Our analysis, results in 1 in 20 islanders Identifying gene mutations and scientific revolution that is occurring help make Precision Medicine a aimed at finding genes with a high being severely color blind better understanding a patient’s in the diagnosis, gene and mutation reality across the medical center. burden of rare variants, has found a took almost three decades disease helps us to better manage identification, and gene therapy of In partnership with several clinical significant signal in retinal dystrophy to identify before modern that disease. The clinical presentation hereditary diseases, if they develop departments, the IGM is breaking genes among the Stargardt-like sequencing technology. of a patient’s disease, or phenotype, knowledge of the possibilities for new ground not only to understand patients (see plot above). We Irene Maumenee, MD depends upon the underlying gene others as well as their disease. Our the clinical applications of genomics continue to explore other eye disease mutation as well as the overall department, along with foundations across the life span of an individual, phenotypes, including nystagmus. genetic makeup and the environment. created and directed by patients, has but also to determine how mutations The IGM will continue to provide Depending on the disease, each of been very successful in promoting can be studied in the laboratory to essential intellectual, technical and these factors may have different ongoing research progress through help develop bioinformatics infrastructure to impacts on the symptoms and advocacy and financial support. strategies for the treatment of advance Precision Ophthalmology™. severity of a disease. Also, more than patients. one gene may produce the same CG CLINICAL GENETIC FIGURE 4.c FIGURE 4.d

TESTING & THERAPIES Pharmacological modulation of vitamin A traffic to the retina is one approach to treating retinal diseases. Toxins called lipofuscin bisretinoids, byproducts of the eye’s visual cycle produced from vitamin A, cause Stargardt disease and contribute to dry AMD. Tinlarebant is a first-in-class oral therapy that prevents the buildup of these toxins. It works by binding to the vitamin-A-binding pocket on a carrier protein, Retinol-Binding With the advancements of genetic Protein 4 (shown in the figure), that testing and diagnosis, it is now delivers vitamin A to the eye. This possible to perform prenatal partially restricts traffic of retinol to genetic analysis at the earliest the eye and inhibits production of stages of pregnancy or even before these toxic bisretinoids. conception. Jeffrey Liebmann, MD Konstantin Petrukhin, PhD

GCATCATT42ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA43CTCAGC

Family Planning/ People who are planning a family For certain conditions, identification Small Molecule Treatments Both young and old individuals can bisretinoids seems to be the primary Genetic Counseling seek genetic testing for a variety of a genetic mutation before suffer from vision loss from macular biochemical defect in Stargardt of reasons, including hereditary pregnancy can allow for dysfunction. Dry (atrophic) age- disease. Our work in recent years led ocular conditions. Parents hope to preimplantation genetic testing related macular degeneration (AMD) to identification of the novel drug better understand the risks of their (PGT). Through in vitro fertilization affects millions of older individuals tinlarebant, which inhibits biosynthesis children developing a condition. (IVF), couples can test embryos for worldwide. Stargardt disease is the of cytotoxic lipofuscin retinoids in Hereditary ocular conditions follow the condition of concern and then most common form of inherited animal models that mimic significant many different inheritance patterns, transfer the unaffected embryos for juvenile-onset macular dystrophy. aspects of dry AMD and Stargardt and identifying the underlying implantation. This greatly reduces Despite the huge unmet medical disease. genetic cause is often the only way the chance of the condition being need, there is no FDA-approved After successfully passing all to accurately inform couples of passed on. In addition, during pharmacological therapy for dry AMD hurdles of pre-clinical development, their child’s risk. Many times, both pregnancy, genetic testing may be and Stargardt disease. tinlarebant has been advanced parents (the parent with disease used to determine if the child may Dry AMD is a multifactorial disorder to human clinical trials. Recently and the unaffected partner) may have or will develop the condition. with several different pathways completed first-in-human single need specialized genetic testing for As we learn more about gene-based contributing to its pathogenesis. Age- and multiple ascending dose the risk to be accurately assessed. therapies, early identification and dependent accumulation of cytotoxic studies evaluated the safety, Proper genetic counseling can inform early treatment of these conditions lipofuscin pigment in the retina tolerability, pharmacokinetics and couples about what type of testing is can improve quality of life and matches the age-dependent increase pharmacodynamics of oral, once- best. decrease vision-related disability. in dry AMD prevalence and thus is a-day tinlarebant in healthy adult frequently cited as one of the critical subjects. Tinlarebant was well pathogenic factors contributing to tolerated and highly effective against the disease progression. Excessive the serum biomarker in these Phase 1 formation of cytotoxic lipofuscin clinical trials. CLINICAL GENETIC FIGURE 4.e TESTING & THERAPIES Human retinal pigment epithelial cell Scanning electron microscopy of a retinal generated from induced pleuripotential stem pigment epithelial cell seeded on inner cells can be generated from patients suffering collagenous layer of human Bruch’s from age-related macular degeneration. After membrane. Ex vivo models of human the correction of the genetic defects with macular degeneration allow us to study gene surgery, monolayers of these cells can the biology of retinal cell transplantation be transplanted into the patient’s subretinal and optimize the conditions for grafted space to replenish the cellular defects and cells to survive and function in the host restore the central sight. Tongalp Tezel, MD subretinal space. Tongalp Tezel, MD

Behavior and function of the grafted cells depends on the host’s subretinal milieu. We have demonstrated that the stiffness and vertical stabilization of the scaffold carrying the grafted retinal cells plays a major role in their subsequent behavior. Failure to optimize the host subretinal environment results in loss of epithelial morphology and specific functions of the grafted cells required to restore sight—a process known as epithelial mesenchymal transition. Tongalp Tezel, MD

GCATCATT44ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA45CTCAGC

Therapeutic Developments Several blinding disorders, such as ideal environment for the grafted and undergo vigorous testing to poor survival for the RPE. macular degeneration, develop as a cells to survive and function. We call detect any residual genetic defect Our researchers have developed in result of the complex interactions of this novel concept “maculoplasty.” and functional deficiency. vitro models to study the fate of multiple genetic, environmental and Our researchers are able to The success of the retinal cell the grafted retinal cells in the host constitutional factors. Meaningful and generate retinal pigment epithelial transplantation depends on subretinal space, which allowed reproducible treatment outcomes for and photoreceptor cells by the engineering of the patient’s them to develop technologies restoring sight can only be achieved reprogramming somatic cells taken subretinal space to create a suitable to rejuvenate the aged Bruch’s if each of these factors are addressed from the patient’s skin or blood. environment for the grafted cells membrane and patch-graft it with before planning human . Using the patient’s own cells prevents to survive and function properly. natural and synthetic matrices that At the Edward S. Harkness Eye the immune response or inflammation The signals that tell retinal pigment mimic the retinal anatomy and offer Institute, we have developed a new that occurs with donor cells. Next- epithelium (RPE) to either remain the best environment to support their comprehensive treatment strategy generation sequencing identifies the differentiated and function as differentiated function. After the cells to restore the sight of the patients underlying genetic defects in these intended, or turn into mesenchymal, are nested in the substrate, they are suffering from macular degeneration cells, which can subsequently be scar-forming cells, comes from the then placed on a biogel also designed and hereditary retinal diseases. corrected with “gene surgery” using matrix they rest on. In patients with at Columbia, which serves to repair This approach involves replenishing the CRISPR-Cas9 system. The result macular degeneration, the Bruch’s any cracks and defects in the the cellular defects of the retina is autologous retinal cells ready to membrane, the natural substrate patient’s native Bruch’s membrane. with stem-cell-derived retinal cells replenish the cellular defects in the for the retinal pigment epithelium, and repairing the defects of the patient’s eye. These retinal cells then is structurally altered by age and extracellular matrices to create an must be prepared under current good environmental damage, resulting in manufacturing practice standards TC “There are many examples where genetic research is being applied to specific ocular diseases and is helping to determine the best care for an individual patient.” — Stanley Chang, MD DISEASE-SPECIFIC FIGURE 5.a FIGURE 5.b AAPPLICATIONS 1861: The indirect ophthalmoscope is invented

1865: Gregor Mendel 2003: Human 2019: The G Genome Project presents his work illuminate trial on inheritance declared complete begins

1953: Watson and 2017: The first in vivo This toddler has type I Peters is normal. Peters anomaly can be 1869: Theodore Leber Crick describe the gene therapy is anomaly of the left eye, caused caused by mutations in the PAX6 describes what is Over the past 150 years, double helix approved by the FDA now generally known we have moved from the by adhesions from the iris to the gene (11p13), the PITX2 gene (4q25- structure of DNA as LCA earliest descriptions of cornea. The result is a poorly formed 26), the CYP1B1 gene (2p22-21), and inheritance to the testing of Descemet’s membrane (a layer deep the FOXC1 gene (6p25). human genetic therapies. within the cornea) and a congenital Danielle Trief, MD, MSc 150 Years Steven Brooks, MD corneal opacity. The girl’s right eye GCATCATT48ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA49CTCAGC

Genetic Therapeutic The loss of function of a gene that pieces of the genetic material (RNA Pediatric Corneal Disease Disorders of the cornea in children higher frequency in certain families Applications is critical to the health of the retina oligonucleotides) can be inserted can be either congenital or acquired, and among children with can be devastating, resulting in into the retinal cells to correct an and many of these diseases and eye rubbing. severe vision loss or blindness. aberration in gene processing. There stem from genetic causes. Some We now have a dedicated monthly Gene therapies now offer hope for is even hope that gene editing at conditions, like congenital hereditary clinic for children with corneal previously untreatable conditions. a molecular level can be used to endothelial dystrophy (CHED), which disorders. Many of these children One of the most extensively correct the underlying mutation itself. causes corneal clouding at birth, also have other ophthalmological investigated applications of gene are caused by a mutation in a single At the Edward S. Harkness Eye or systemic diseases. Care of these therapy has been in early-onset gene. Other congenital corneal Institute, all of these approaches are children is always interdisciplinary, retinal degenerations. This research conditions, like Peters anomaly, are under laboratory investigation, and whether that means working with has been so successful that the FDA associated with mutations in multiple some are being studied in clinical an ophthalmologist in the field of recently approved one such agent, genes. trials. The application of these glaucoma or retina, or a pediatrician Luxturna (voretigene neparvovec), cutting-edge therapies requires Today, we are making rapid advances with an entirely different medical for use in a specific form of childhood genetic testing, the design of precise in our understanding of pediatric specialty. By understanding the retinitis pigmentosa (RP). and personalized therapeutic agents, corneal disease. While we are able genetic origins of these complex

Overleaf: Color- Several promising strategies can be and a team of clinical specialists to link some conditions directly to diseases, we will be able to develop coded quantitative employed to restore the function capable of delivering the agents to their genotypes, we understand more targeted therapies. autofluorescence image of the damaged gene in the eye. the eye. that others are likely the result of overlaid by structures of Viruses, also known as viral vectors, an interplay between genetic and some of the bisretinoids can be engineered to deliver a normal environmental factors. Keratoconus, that are the source of copy of the gene to affected cells, for instance, which often begins to short-wavelength fundus autofluorescence as with Luxturna. Specifically, small manifest in puberty, can be seen in Janet Sparrow, PhD DISEASE-SPECIFIC FIGURE 5.c FIGURE 5.d APPLICATIONS A

Real-time confocal microscopy Although more commonly seen images of the corneal stroma among adults, glaucoma can also following topical cross-linking, A photograph of the eye of an infant affect newborns and infants, leading with progressive keratocyte G with congenital glaucoma showing a to lifelong . Primary changes over 2 months. The normal hazy cornea (the front window of the congenital glaucoma affects children keratocytes (bright white oval eye) with linear streaks (Haab’s striae) between birth and 3 years of age in nuclei in panel A) initially undergo from the high intraocular pressure that the absence of other abnormalities; cell death followed by repopulation stretches and damages the eye. developmental glaucoma is Steven Brooks, MD and activation with various degrees accompanied by abnormalities of C. Gustavo De Moraes, MD, MPH, PhD of cytoplasmic and extracellular T the iris and/or the eye’s drainage matrix hyper-reflectivity as shown system, and sometimes also by in panel B (1 week) and panel C systemic conditions such as dental (1 month). By 2 months (panel D), abnormalities, intellectual disability, the keratocyte repopulation and and musculoskeletal malformation. normalization is complete. David Paik, MD CCongenital & Juvenile Genetic testing plays an important Leejee Suh, MD Glaucoma role in the prompt identification GCATCATT50ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA51CTCAGC

Keratoconus Keratoconus, a progressive eye ranging treatment applications and treatment of these types of described, myocilin gene (MYOC), is disease in which the cornea thins and beyond keratoconus, including the glaucoma. For instance, more highly prevalent among patients with begins to bulge into a cone-like shape, progressive myopia resulting from than 50% of children with ocular juvenile glaucoma. An estimated 8%- typically develops in a person’s late anesthesia injection in the sub-Tenon’s abnormalities caused by either PITX2 63% of unrelated juvenile glaucoma teens or early twenties, and results space, and difficult-to-treat corneal or FOXC1 mutations have glaucoma patients have MYOC mutations. New in high degrees of astigmatism and infections involving multi-drug- characterized by high eye pressure. evidence suggests genetic testing inability to correct a person’s vision resistant organisms. These are genes that in healthy of family members of patients despite glasses and contacts. individuals help regulate cell division. with juvenile glaucoma can lead to Another important gene with a similar earlier detection of milder forms of With the help of a grant from the role is called PAX6, and its mutation the disease. Moreover, new genetic National Eye Institute, scientists can cause a severe form of glaucoma therapies, namely gene editing at Columbia Ophthalmology associated with a rare type of kidney (CRISPR), have shown promising are developing a topical tissue- cancer. therapeutic outcomes in mice and strengthening treatment for could potentially be tested in humans keratoconus that involves the Juvenile open-angle glaucoma is a in the near future. application of cross-linking agents highly inheritable form of the disease to the corneal surface. This cross- that also affects individuals at an linking solution could have far- early age—typically between 4 and 35. Patients often have multiple family members with early-onset, severe forms of glaucoma. One of the first glaucoma-associated genes to be DISEASE-SPECIFIC FIGURE 5.e FIGURE 5.f APPLICATIONS

Pigment dispersion syndrome is characterized by release of pigment from the iris pigment epithelium, which is the posterior- Exfoliation material consists of most layer of the iris. This results in fibrillo-granular deposits that the characteristic, midperipheral, appear clinically as a white, radial, iris transillumination defects snowflake-like material on the pictured here. The pigment that surface of the lens and other is released can clog the eye’s structures of the anterior segment, drainage system, leading to a such as the ciliary body, iris and buildup of ocular pressure and zonules. A lysyl oxidase-like 1 causing pigmentary glaucoma in (LOXL1) gene defect is necessary approximately 30-35% of patients. for the development of the disease, While clustering in families occurs, but a gene-environment interaction the specific gene defect remains is thought to be responsible for unknown and is the focus of an the differences in worldwide ongoing research program. prevalence of the disease across Dana Blumberg, MD, MPH continents and latitudes. Y. Shira Kresch, OD Jeffrey Liebmann, MD

GCATCATT52ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA53CTCAGC

Pigmentary Glaucoma Pigmentary glaucoma (PG) accounts Here at Columbia, we have led many Exfoliation Syndrome Exfoliation syndrome (XFS) is Over a decade ago, genome-wide for 1-2% of all open-angle , of the recent studies that have the most common identifiable of association studies identified and typically affects nearsighted used next-generation sequencing secondary open-angle glaucoma, the first variants associated with individuals between the ages of to identify the genes involved with accounting for up to 25% of open- exfoliation syndrome on the gene 20 and 50 years. Although the similar complex disorders of the eye, angle glaucoma worldwide and LOXL1. More recently, at least six phenotype of PG has been well and we are now applying the same posing a greater risk of visual other genetic loci (CACNA1A, understood since its first description techniques to search for the genes impairment than other forms of FLT1-POMP, TMEM136-ARHGEF12, in 1940, we know very little about its that underlie PDS and PG. Our large open-angle glaucoma. AGPAT1, RBMS3 and SEMA6A) genetic predisposition. database featuring state-of-the-art have been pinpointed as associated Exfoliation material appears as white, imaging of patients with PDS and with a high risk for XFS. Columbia Pigment dispersion syndrome flaky material in the anterior segment PG, along with a newly established University’s Glaucoma Division (PDS), which involves the release of of the eye. This material accumulates collaboration with the Columbia is at the forefront of the genetic pigment from the back part of the within the eye’s drainage system, Institute of Genomic Medicine, will study of XFS, managing some of iris into the eye’s anterior segment, obstructing its flow and causing help us shed light on the genetic the most complicated patients with is a secondary cause of elevated an increase of intraocular pressure, origins of these conditions and this condition and working to help intraocular pressure. Individuals with resulting in glaucomatous damage customize care for those at risk. identify family members at high PDS have a 35-50% lifetime risk of of the optic nerve. This process risk of developing glaucoma and developing pigmentary glaucoma. causes telltale pigmentary changes provide tailored treatment. Studies have suggested that PDS in the eye and notoriously weakens may result from a combination of intraocular structures. This creates a mutations in multiple genes. high-risk environment for intraocular procedures, such as cataract surgery, CG requiring highly skilled surgeons. DISEASE-SPECIFIC FIGURE 5.g FIGURE 5.h APPLICATIONS

Disease severity in ABCA4 associated macular degeneration: (A) The spatial distribution of flecks as a function of age is a reflection of lipofuscin accumulation. Confluence of flecks in the retina marks a critical transition stage culminating with retina- wide involvement. (B) Geographic (black lesions) is defined by the simultaneous loss of RPE and photoreceptor cells. (C) Quantitative autofluorescence (qAF) is an indirect Spectral-domain optical coherence OCT-A image strikingly demonstrates measure of RPE and photoreceptor tomography (SDOCT, left), and a mature choroidal neovascular outer segment lipofuscin, which optical coherence tomography membrane. Precise genetic analysis progressively accumulates due to angiography (OCT-A, right) of a coupled with high-resolution retinal ABCA4 dysfunction in accordance patient with neovascular age-related imaging may allow us to develop with disease severity. macular degeneration. The SDOCT molecularly targeted therapies. Rando Allikmets, PhD shows elevation of the retinal pigment Royce Chen, MD Janet Sparrow, PhD epithelium, and the corresponding Stephen Tsang, MD, PhD GCATCATT54ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA55CTCAGC

Age-Related Macular Age-related macular degeneration Although there is no simple Retinal Degenerations More than 300 genes have been At Columbia Ophthalmology, we Degeneration (AMD) is a leading cause of blindness genetic inheritance pattern for the associated with inherited retinal have made significant progress in individuals over the age of 60 development of AMD, the disease dystrophies, which affect vision in in understanding the disease- around the world. It is an acquired certainly runs in families, as a family approximately 1 in 2,000 people. One causing genetic variation in ABCA4, degeneration that specifically affects member of a patient with AMD of these genes is the ABCA4 gene which has substantially improved the macula, the part of the retina is at least three times more likely and was first identified at Columbia diagnostic screening. Thanks to responsible for central vision. AMD to develop AMD. Of the multiple Ophthalmology. More than 1,000 vast improvements in imaging is classified as non-neovascular, genetic alterations that have been disease-associated variants in ABCA4 methods, such as optical coherence characterized by drusen (subretinal found to confer a greater risk for have since been described. tomography, autofluorescence deposits) and geographic atrophy, the development of AMD, the (AF) and adaptive optics, we can Certain ABCA4 mutations cause or neovascular, characterized by polymorphisms Tyr402His at 10q26 precisely categorize ABCA4 disease autosomal recessive Stargardt the formation of new vessels that (Complement factor H locus), and quantitatively measure its disease (STGD1), the most frequent may leak into the retina, bleed, and and Als69Ser (LOC387715) may progress. The ABCA4 locus serves form of inherited juvenile macular eventually cause irreversible scarring. be responsible for the majority of as a model of complex genotype/ degeneration. People with STGD1 In recent years, therapies have been the genetic risk of AMD. Columbia phenotype associations not only for experience slowly progressing central introduced that have improved our Ophthalmology is a world leader Mendelian eye diseases but for the vision loss, usually beginning in care of individuals with AMD. in discovering genetic variants entire genetic research field. When their teens. Almost all people with responsible for AMD, developing novel we know the exact genetic cause of a STGD1 will become legally blind. imaging techniques for earlier disease disease and its clinical phenotype, we Other phenotypes caused by ABCA4 diagnosis, and providing vision-saving can make a proper diagnosis, which mutations range from late-onset, mild treatment to thousands of patients. is crucial for genetic counseling, cases of central atrophy to very predicting disease progression and early-onset degeneration throughout selecting patients for clinical trials. the retina. DISEASE-SPECIFIC FIGURE 5.i FIGURE 5.j APPLICATIONS

Retinoblastoma was the first disease in which an abnormal gene was found to be associated with cancer. A Genetic testing can be performed to determine if a mutation is inheritable. This information helps to assess risks for second cancers and is used in G family planning.

Color fundus photograph from a retinitis pigmentosa patient with Choroidal melanoma can be mutations in the gene encoding evaluated genetically to gain Cyotochrome P450, Family prognostic information. Before 4, Subfamily V, Polypeptide 2 treatment, a fine-needle biopsy (CYP4V2). provides the samples needed for Stephen Tsang, MD, PhD gene profiling and to assess the patient’s risk for metastatic disease. Brian Marr, MD

GCATCATT56ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA57CTCAGC

Retinitis Pigmentosa Retinitis pigmentosa (RP) is a group gene must be replaced without Ocular Oncology Ocular oncology has a long The uveal tract consists of the iris, of hereditary disorders that cause altering the healthy one. Columbia and storied history at Columbia ciliary body and choroid. Uveal progressive degeneration of the Ophthalmology is pioneering genetic Ophthalmology. Of eye cancers, melanoma is the second most photoreceptors and retinal pigment surgery and has developed a novel retinoblastoma is the most common common type of melanoma, affecting epithelium (RPE), resulting from technique for the gene editing tool primary intraocular tumor in children, six per million people in the United mutations in any one of more than 50 CRISPR, which has successfully with approximately 350 new cases States. Currently, it can be managed genes. These disorders typically first restored retinal function in mice occurring in the United States yearly. locally with radiation or surgical appear in childhood and, because of afflicted by autosomal dominant RP. The retinoblastoma gene found on treatment. Despite high success the many genes involved, can have a chromosome 13 occurs sporadically with control of the primary tumor, There are now at least six clinical widely varying course. or can be passed down from affected metastatic disease can occur in up to trials underway studying gene parents. This gene was the first 50% of patients. Genetic analysis of Mutations in the RPE65 gene account therapy as a treatment for RP, with discovered oncogene linking genetic uveal melanoma has revealed certain for a number of cases of early-onset two of those trials headquartered at mutation with cancer. Genetic testing mutations that are predictive of retinal dystrophy, and positive results Columbia Ophthalmology. These trials can be done on affected individuals developing metastatic disease. Fine- from gene therapy trials for RPE63- focus on X-linked RP, an inherited and family members that can help needle aspiration biopsy at time of mediated retinal dystrophy led to condition caused by mutations in the predict risks for disease and risk primary tumor treatment can be used the 2018 approval of voretigene RPGR gene that causes progressive for second cancers. If a germline to obtain the genetic information neparvovec-rzyl (Luxturna), the first vision loss in boys and young men. mutation is found in an individual, from the tumor and predict this gene therapy for any disease to be Another precision stem cell trial is then the risk for second cancer and risk. The genetic information can be approved in the United States. But in the planning phase, focused on transmission of the gene to offspring used to adjust systemic screening autosomal dominant forms of RP patients with RP associated with is known, and patients can be schedules and permit eligibility into pose a more difficult challenge for mutations in the MERTK gene. counseled, managed and screened to adjuvant clinical trials. gene therapy, because the defective achieve the best outcomes with the TC disease and its sequelae. “The advent of next-generation sequencing and advanced imaging has enabled scientists to elucidate most of the genetic variation that is causal in monogenic eye diseases and has facilitated significant advances in complex disorders.” — Rando Allikmets, PhD GENE DISCOVERY FIGURE 6.a FIGURE 6.b

Quantitatively defined A clinical trajectories

Study scheme for integrated phenotype/genotype correlation studies. Phenotype/genotype G correlation matrix for patients with a ABCA4 mutation based on

Genotype preliminary genetic and clinical pathogenicity data is presented in the center. Quantified clinical data obtained will be correlated with genetic data obtained and analyzed. Recent evidence suggests that gene set (left panel) is mostly involved in the Predicted pathogenicity of non- coding allele Integrated data analysis will refractive eye development and regulation of baseline refractive development and result in deducing the variant the development of myopia are determines the overall trajectory of refractive eye Functional validation class and relative pathogenicity controlled by two overlapping gene development. The second gene set (right panel) of DI variants, which are then sets. This figure shows key genes and is chiefly responsible for the gene-environment Patient groups for clinical trials functionally tested. top biological processes involved in integration underlying refractive error. Rando Allikmets, PhD refractive eye development. The first Andrei Tkatchenko, MD, PhD

GCATCATT60ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA61CTCAGC

Intersection of Clinical & Genetic testing is performed on whether directly based on genes or Myopia Genetic factors modulate the networks and signaling pathways Research Genetics a patient’s DNA to reveal known the functional pathways they direct. impact of the visual environment on underlying the development of mutations in established disease Direct application of genetic research refractive eye development and play human myopia. genes. Those data come from basic data is not always straightforward an important role in the development Combining systems genetic studies and clinical genetic research, which is even for monogenic disorders, such of myopia (nearsightedness). We in animal models and humans, constantly adding to our knowledge as Stargardt/ABCA4 disease, where have recently found that over 900 Columbia Ophthalmology has of genetic causality of not only resulting clinical complexity takes retinal genes, initially identified characterized the genetic networks monogenic, Mendelian diseases but time to be approved by certified labs in the mouse model of myopia, and signaling pathways involved in also complex disorders such as age- performing genetic testing. But the are subjected to genetic variation refractive eye development. Using related macular degeneration and real revolution ongoing in genetic causing myopia in humans. These that information, we have developed glaucoma. While genetic testing of research and gene-based therapies genes are associated with over 50 a pharmacogenomic pipeline for single-gene diseases is established allows optimism for substantial signaling pathways, many of which anti-myopia drug development. This reasonably well, the necessity of advances also in the genetic testing are involved in the processing of approach already has produced testing complex disorders is still field. positive and negative optical defocus several promising candidates, which under serious discussion. The main known to regulate refractive eye are currently being studied in the arguments against testing late- development. laboratory. onset, complex traits are ambiguity Overleaf: AAV-based Importantly, these signaling pathways of results and lack of treatment CRISPR therapy in a were found to be highly conserved rhodopsin mutant mouse. options. However, the development across distant vertebrate species, The mouse model was of genetic research is constantly including chickens, mice, marmoset crossed with Brainbow 2.1 adding to our knowledge of causality monkeys and humans—suggesting reporter mouse in order to and also provides ample targets that systems genetics studies in evaluate the transduction for developing treatment options, efficiency. animal models can identify genetic Stephen Tsang, MD, PhD GENE DISCOVERY FIGURE 6.c FIGURE 6.d

A retinal photograph demonstrating characteristic findings seen in patients with retinitis pigmentosa, including “bone spiculing” in peripheral retina, which are the fine, lacey A black changes. In addition,

the retinal blood vessels are units qAF intensity attenuated, and the optic nerve is slightly pale. Quantitative Fundus Stephen Tsang, MD, PhD Autofluorescence GCATCATT62ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTGCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA63CTCAGC Retinitis Pigmentosa Associated with more than 80 for the treatment of RP. Best Disease Best disease is caused by mutations Color-coded quantitative fundus genes, retinitis pigmentosa (RP) is a Because rods are among the most in the gene BEST1. Deficiency in autofluorescence (qAF) images. heterogenous condition characterized metabolically active cells in the body, the BEST1 protein leads to fluid In the image acquired from the by the breakdown and loss of rods, burning glucose to release energy, it accumulation in the subretinal space patient diagnosed with Best disease, the photoreceptors in the retina that is possible that diseased rods could leading to a dome-shaped lesion the central lesion is a paler blue, enable peripheral and night vision. be restored by reprogramming their separating neural retina from retinal indicating higher-intensity fundus Over time, the deterioration of rods sugar metabolism. At Columbia, pigment epithelium. Scientists at autofluorescence. Outside the lesion, compromises the function of cones, we have shown that this precision Columbia have determined how the levels are not different than in the color-sensing photoreceptors, metabolic reprogramming can mutations can cause the protein the healthy eye. The graph above leading to night blindness, tunnel improve the survival and function of T to malfunction. The scientists have shows that qAF values for Best vision and, eventually, complete affected rods and cones in at least also demonstrated that, contrary to patients (red circles) are within the blindness. one type of RP. Since many forms of what had been assumed, a retina- range of healthy eyes (black lines). the disorder have the same metabolic wide increase in lipofuscin does not Janet Sparrow, PhD Although gene therapy has shown error, precision reprogramming could occur. Instead the central egg-yolk- Stephen Tsang, MD, PhD promise in RP, it is complicated conceivably be applied to a wide like lesion acquires autofluorescence by the fact that defects in at least range of RP patients. secondary to 80 genes have been linked to the C damage. disorder, and each genetic defect would require a different therapy. As of 2020, there are about 20 clinical trials underway studying different gene supplementation approaches “Clinical trials are designed to test new approaches to the treatment of patients with eye disease. The trials are conducted in phases that build on one another, the goal being to establish the safety and effectiveness of the interventions.” — Stephen Tsang, MD, PhD CLINICAL TRIALS FIGURE 7.a FIGURE 7.b

The Columbia University Irving Medical Center developed RecruitMe, a recruitment tool meant to connect those who A want to participate in clinical trials or research studies to T the researchers that are conducting them. Lisa Hark, PhD, RD

GCATCATT66ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA67CTCAGC

Choroideremia Choroideremia is an example of Choroideremia-affected males Natural History Many ocular conditions have a chron- and identify individuals at greatest an ocular disease that is currently present with progressive Studies ic and progressive nature. Therefore, risk of becoming visually impaired. In being investigated by both clinicians degeneration of retinal cells and the goal of treatment is to slow or both cases, the goal of these studies and scientists within Columbia underlying choroid (left). Preserved halt the speed of progression, as is is to generate pristine, reliable data Ophthalmology. Choroideremia is an cells in the center of the retina are the case for diseases such as glau- for the design of clinical trials testing X-linked recessive disorder affecting visible as speckled islands in fundus coma, macular degeneration and novel therapies that could improve approximately 1 in 50,000 males autofluorescence images (right). retinal dystrophies. Natural history their outcomes. Patients who partici- with disease onset in affected males Janet Sparrow, PhD studies are research investigations pate in natural history studies may be

occurring in childhood. Loss of sight in two multicentered, clinical trials in which patients affected by these offered the opportunity to participate progresses to legal blindness by the focused on choroideremia. One chronic, progressive conditions are in subsequent clinical trials that could fourth decade. Our investigators of these studies’ aims is to collect followed for relatively long periods of potentially alter the course of diseas- have discovered a phenotype of information on the natural history time to determine the course of the es for which no treatment is current- choroideremia that is also expressed of the disease so as to establish disease. For conditions with standard ly available. For treatable diseases, in some carriers of the disease diagnostic measures that can therapies, such as glaucoma, nat- they can help identify safer and gene. This means that characteristic be used to measure treatment ural history studies determine the more effective forms of therapy. The findings associated with the disease outcomes during the development average rate of progression among Clinical Trials Unit of the Department are seen not only in confirmed of novel therapies. The objective patients while they are treated, as of Ophthalmology helps design and patients but also in women that are of the second clinical trial is to well as how much variability there is conduct a number of natural history Overleaf: Structural model “carriers” of the genetic mutations evaluate the safety and tolerability between patients with regard to their studies that will serve as the basis for of the genome surgery but never develop the disease of a gene therapy approach to outcomes. For conditions that lack new therapies. These trials can make nuclease Cas9 interacting themselves. standard therapies, such as “orphan” the difference in preventing blindness with a gRNA. the treatment of patients having a diseases, these studies help better during a patient’s lifetime. Gabriel Velez, MD, PhD; The Columbia Department of genetically confirmed diagnosis of Vinit Mahajan, MD, PhD; Ophthalmology has participated choroideremia. determine how rapidly they progress Stephen Tsang, MD PhD CLINICAL TRIALS FIGURE 7.c A FIGURE 7.d G T

CT scan of the orbits showing surrounding the eye), we do not yet enlargement of the extraocular understand why some patients with muscles in the setting of thyroid eye Graves’ disease develop thyroid eye disease. Lora Glass, MD disease, while others do not. GCATCATT68ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA69CTCAGC Clinical Trials Unit The Clinical Trials Unit (CTU) in The trials now underway in the Microbiome, Columbia Ophthalmology works Some studies suggest that the the Department of Ophthalmology Department focus on developing Thyroid Disease & with physicians and researchers from diversity and ratios of intestinal The All of Us Research supervises all clinical research at the novel drugs, innovative devices and Thyroid Eye Disease across the entire Columbia University bacteria (the microbiome) have an Program is a momentous effort Edward S. Harkness Eye Institute. techniques, and new diagnostic tools. to accelerate discovery science and impact on Graves’ disease and other to advance individualized The CTU staff includes 12 full- They range from smaller Phase I and to promote health for all who seek autoimmune conditions. Columbia prevention, treatment and care time clinical research coordinators Phase II trials assessing safety and care. An example of such is found Ophthalmology is working with for people of all backgrounds. who manage the entire process of tolerability, to large Phase III trials in the research being conducted in colleagues in , General This national consortium is led human research, including protocol aimed at determining the efficacy diseases associated with the thyroid Surgery, Gastrointestinal Disorders, by the Columbia University development, institutional review of a drug, device, or gene therapy gland. The thyroid gland, located in and Precision & Genomic Medicine Irving Medical Center with the board preparation and submission, technique for conditions including the neck, produces a hormone called to unravel this mystery. We are in aim to enroll 1 million diverse participant recruitment, clinical trial age-related macular degeneration thyroxin that helps to regulate body the midst of a multi-institutional people with differences in enrollment, study procedures and (AMD), Stargardt disease, metabolism. Graves’ disease of the study of the microbiome diversity lifestyles, environments, and database management. Principal achromatopsia, glaucoma, retinitis thyroid can be life-altering, often of patients with Graves’ disease, biological makeup, including investigators lead our research pigmentosa and choroideremia. requiring radioactive iodine to reduce patients with Graves’ disease and genes. It is an example of the studies, and research coordinators Long-term studies of retinal thyroxin production, surgery and thyroid eye disease, and matched focus on Precision Medicine aid in interfacing with sponsors and degenerations, corneal disease, the need for chronic medications. counterparts without either condition, that embraces the entire regulatory agencies. All research and structure and function of the Its highly associated counterpart, in an effort to better understand Medical Center. studies require Institutional Review optic nerve often span many years thyroid eye disease, can cause the whether microbiome content—in the C. Gustavo De Moraes, MD, Board (IRB) approval from Columbia’s and require the close coordination eyes to appear prominent and in some eye or gastrointestinal tract—may MPH, PhD Human Research Protection Office, of study patients, coordinators, cases can be disfiguring and vision- be responsible for elevated risks of which requires adherence to rigorous investigators and monitoring threatening. Though we know that thyroid eye disease presentation ethical guidelines in order to protect physicians. antibodies to the thyroid gland can and severity. This is an example of a all participants. also attack orbital tissues (the tissues collaborative clinical trial that extends far beyond ophthalmology. “The Applied Genetics and Precision OphthalmologyTM revolution will require a coordinated effort among scientists, clinicians, educators and institutes to push forward into a new era of individualized treatment and cures for blinding eye diseases and restoring vision to those who have lost it.” — Jeffrey Liebmann, MD THE FUTURE TRAINING & EDUCATION

The Roy and Diana Vagelos Education Center at the Columbia University Irving Medical Center A provides a state-of-the-art venue for educating the physicians and G scientists of the future.

GCATCATT72ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA73CTCAGC

The Future Begins with Genetics Residency and Fellowship become board certified in both that allows for board-eligibility ongoing educational opportunities Science Course in Ophthalmology ophthalmology and human genetics. Education To place the field of Ophthalmic ophthalmology and , in ophthalmic genetics for all regularly invites some of the most This training pathway will be offered Applied Genetics on solid clinical provides an ideal way to train the of ophthalmology, recognized experts in inherited to future ophthalmologists who ground for the future and to better future ophthalmic geneticists to creating a higher standard eye diseases to lecture to our recognize the impact that medical serve our patients, we recognize deliver the highest-quality care to for the education of future residents, fellows and students and molecular genetics will have that ophthalmology needs to be patients. This approach will allow our ophthalmologists and a model for from different parts of the world. on the field. Our approach will the next specialty to offer the ophthalmic geneticists to effectively other training programs. Within These educational opportunities prepare dual-trained physicians option of formal training in the direct the multiple facets of an our residency program, we have allow both novices and experts who can tackle future challenges fundamentals of human genetics. ophthalmic genetics team, whether given residents an opportunity to learn more about ophthalmic in care, diagnostics and therapy in With leaders in ophthalmology it be communicating with molecular to learn from leaders in the field genetics and to create leaders ophthalmic genetics. and genetics at the helm of this pathologists, genetic counselors, at Columbia and elsewhere. who will bring cutting-edge care effort, Columbia Ophthalmology Dual training in medical genetics patients, the health care industry, Within the department, we have to the clinic. plans to be the first ophthalmology has been successfully implemented foundations or governmental created multiple educational department to provide formal in other fields of medicine in agencies. opportunities with emphasis on ophthalmic genetics. These opportunities for dual training in which genetics is fundamentally Incorporating genetic education into Overleaf: Crystal structure ophthalmology and medical genetics. intertwined with the delivery of resident and fellowship education conferences create an opportunity of cellular retinaldehyde- for ophthalmic geneticists at all A combined residency or fellowship medical care, such as pediatrics In addition to providing a formal path binding protein, a levels to convene and discuss some track will prepare our trainees to and maternal-fetal medicine. A to dual training in ophthalmology component of the visual combined ophthalmology-medical of the most challenging cases in cycle that binds the 11-cis- and genetics, we also provide genetics residency track, or a ophthalmic genetics. Moreover, our retinal (orange spheres) internationally recognized Basic chromophore. post-residency fellowship track Tingting Yang, PhD; Stephen Tsang, MD, PhD; Janet Sparrow, PhD THE FUTURE PHILANTHROPIC A PARTNERSHIPS G

New Drug Development from A B Pharmacogenetics Exfoliation glaucoma, accounting C for 25% of all glaucoma worldwide, Cells from patient with exfoliation is a complex late-onset disease glaucoma were exposed to the characterized by abnormal production compound solvent (A) or test and accumulation of fibrillary deposits compounds (B-D). Compound called exfoliation material (XFM) B reduces the intensity of red in the anterior segment of the eye. C D staining, indicating that it facilitates Given the causative role of XFM in the Chemical structure and model substrate degradation and thus pathogenesis of exfoliation glaucoma structure of nicotinamide, an T may be considered as a potential (XFG), it seems reasonable to suggest important form of vitamin B3. It treatment. Compounds C and D that inhibition of the formation of has an amide (NH2) component, increase the intensity, which indicates exfoliation aggregates represents a or group of unique biochemical the undesired inhibitory activity. solid treatment strategy for XFG. properties compared to the other Konstantin Petrukhin, PhD A diminished capacity of cells in forms of vitamin B3.

GCATCATT74ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA75CTCAGC

The Future Is Now: The ability to create the programs and Applied Genetics into tools that the eye for degradation of denatured studies are performed in a cell line health and prevented structural and The Brown Initiative and teams for the future depends benefit patients. and misfolded proteins seems to established from a patient with functional loss of retinal ganglion on collaboration among research exfoliation glaucoma. We also plan cells, despite continued elevation Gene Discovery underpin the development of protein scientists, clinicians, patients, aggregates in XFG. As in many other to conduct animal studies in mouse of intraocular pressure. In the same A well-characterized phenotype institutions and philanthropists. The age-related diseases, aggregate and rabbit animal models in order to mouse model, gene therapy targeting facilitates genetic studies of any Brown Initiative, made possible by accumulation in XFG seems to be establish in vivo activity of the test the retinal pathway that produces disease. Pigmentary glaucoma, a a generous donation by Shirlee and caused by aberrations in cellular compound. nicotinamide protected 70% of subtype of open-angle glaucoma, has Bernard Brown, longtime supporters degradation—specifically, in the mice from glaucoma damage over a striking and very specific clinical Nutritional Supplementation: of the Department of Ophthalmology mechanism of autophagy. We recently Vitamin B3 Study 12 months—and the combination presentation and primarily affects and glaucoma research, seeks to identified a drug-like lead molecule of gene therapy with nicotinamide young adults in the prime of life. The earliest evidence of glaucoma enhance knowledge across a broad CU1079 as a potent lysosomal ion supplementation produced the best This study goal seeks to determine damage occurs in mitochondria, spectrum of glaucoma research and channel modulator that can improve protection of all. This identification of the genetic basis of this subset of which are present in every cell in our translate this newfound information degradation of misfolded and the cellular mechanisms underlying glaucoma by identifying the genes bodies. Mitochondria are critically into novel, patient-friendly treatments. aggregated proteins in XFG, thus early glaucoma progression has that cause it. After our clinicians important for the optic nerve cells To accomplish these goals, glaucoma preventing the formation of exfoliation opened a new avenue for exploration, identify patients with this disease because they are responsible for researchers are focusing on three deposits. Our immediate objective and we are in the midst of human and blood samples are taken, our creating the energy that each areas of intense interest: gene is to perform characterization of clinical trials that will assess basic science genetics research team of these cells uses. This study is discovery, development of new CU1078 in order to develop data whether neurodegeneration can explores the genome of each patient focused on the clinical implications of medications, and devising ways of required for submission of the NIH be treated with vitamin B3 dietary to find the common gene defects promising basic research in vitamin protecting the optic nerve from grant application that will support supplementation, along with other among them to serve as target B3 (nicotinamide) on glaucoma. It damage. This unique program serves optimization of this lead molecule compounds to promote mitochondrial candidates for research to identify the has been demonstrated in a mouse as a model for accelerating and and developing the XFG drug. Drug health. proteins encoded by the genes and model that at the lowest dose tested, translating Precision OphthalmologyTM find ways to overcome them. nicotinamide enhanced mitochondrial THE FUTURE A VISION OF THE FUTURE

patient is offered the opportunity to participate in our gene discovery research program, with their A demographic and clinical data stored in a database and their DNA samples maintained in Columbia Ophthalmology’s BioBank. As more genes involved with ocular disease G are identified, we will have a record of these patients and be able to screen their test results for the new genes.

For patients whose eye disease has been linked to a specific gene, his or her case will be presented to a review panel of experts that is responsible for developing a management plan based on the patient’s genetic findings. GCATCATT76ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTCGGTAGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA77CTCAGC

Building an Ophthalmic Columbia Ophthalmology’s Applied The Applied Genetics Initiative builds Genetic Therapy Institute Genetics Initiative is one of only on an established system of referrals a handful of genetic eye disease to Precision OphthalmologyTM studies programs in the world. We offer ongoing in the Department, the people with suspected genetic eye University and around the world. Our disorders access to a comprehensive past and ongoing gene discovery range of services, including screening, and intervention programs make Images of the entrance diagnostics, genetic counseling and Columbia Ophthalmology a center for to the Edward S. Harkness research study participation, all under innovation in this rapidly emerging Eye Institute and the one roof. Patients can be referred to and critically important field and an Roy and Diana Vagelos the Applied Genetics Initiative either ideal home for a world-class clinical Education Center. by an outside clinician or through ophthalmic genetics program. internal referral by another Columbia physician. All patients undergo diagnostic testing and DNA analysis, along with genetic counseling.

If the analysis is negative—that is, there is no currently known gene associated with their condition—the CT DEPARTMENT STATISTICS

MAJOR FUNDED PROGRAMS Anne Stean Bernard and Shirlee Brown Flanzer Eye Basic Science Course Foley Retina Corneal Glaucoma Initiative Center in Ophthalmology Research Fund Research Fund The Russell Berrie Diabetic Retinopathy Research Unit Robert Burch Family Stephen Ross Edith and Denton C.V. Starr Jonas Vision Bernard and Shirlee Eye Center Pediatric Eye McKane Memorial Fund The Starr Foundation Scholarship Research Brown Glaucoma Center Retinal Research Unit Fund Laboratory Research Laboratory Gloria and Gloria and Louis Louis Flanzer The Louis V. Gerstner Jr. Foley Clinical Florence and Herbert Flanzer Vision Amphitheatre Clinical Research Center Care Center Retina Fellowship Kirby Fellowship Irving Translational Vision Jean and Kent Sheng Jonas Children’s in Vision at Columbia Research Laboratory Glaucoma Fellowship Vision Care University

FEDERAL FUNDING BEST DOCTORS ABSTRACTS & PUBLICATIONS ONGOING CLINICAL TRIALS PATIENT VISITS ANNUALLY SURGERIES ANNUALLY $10.4 M 28 322 40 >100,000 >5,000 Physicians in National In the Past Year & Regional Rankings

GCATCATT78A TTC GGTTA CA CGATCCA G AGTG CGGTAA CC TTAA CCTCA GAGTGAGTT CTA TTTCGGTAG CATCATTC TATTCGGTTT ACACGGCGG TAACCTTAA CA79CTCAGC

PROFESSORSHIPS Edward S. Harkness Professor and Chair: PROFESSORSHIPS & DIRECTORSHIP 33% 272 26 10 30% G.A. (Jack) Cioffi, MD Total Staff Part-Time Clinical William and Donna Acquavella Professor: A. Gerard DeVoe – B. Dobli Srinivasan Director and Faculty Faculty Fellows Rando Allikmets, PhD of the Harkness Eye Clinic: Jason Horowitz, MD 46 12 16 Malcolm Aldrich Research Professor Full-Time Ophthalmology Postdoctoral Jules and Doris Stein Research to Laszlo T. Bito Professor: Faculty Residents Fellows Prevent Blindness Associate Professor: Stephen Tsang, MD, PhD Xin Zhang, PhD Shirlee and Bernard Brown Professor: Miranda Wong Tang Associate Professor: Growth In PATIENTS FROM 87 COUNTRIES Growth In Jeffrey Liebmann, MD Overall Overall Leejee Suh, MD Robert L. Burch III Professor: K.K. Tse and Ku Teh Ying Professor: Departmental Grant Simon John, PhD Budget Funding Stanley Chang, MD

Over 5 Years Over 3 Years Chang Family Professor: Tongalp Tezel, MD Anne S. Cohen Professor: NAMED LECTURESHIPS Steven Brooks, MD Stanley Chang, MD Lectureship Jean and Richard Deems Professor: Arthur Gerard DeVoe, MD Lectureship G.A. (Jack) Cioffi, MD Zacharias Dische, MD Lectureship John H. Dunnington, MD Lectureship Anthony Donn Professor: Janet Sparrow, PhD Max Forbes, MD Lectureship Barbara and Donald Jonas Lectureship John Wilson Espy, MD Professor: David Pearce, MD Memorial Lectureship Brian Marr, MD George K. Smelser, MD Lectureship Herbert and Florence Irving Professor Abraham Spector, MD Prize Lectureship

Helen and Martin Kimmel Assistant Professor: Florence Epstein Teicher Lectureship Royce Chen, MD Ulrich Ollendorff, MD Lectureship THE DEPARTMENT DEPARTMENT OF OPHTHALMOLOGY FACULTY

G.A. (Jack) Cioffi, MD Irene Maumenee, MD Edward S. Harkness Professor; Jean and Richard Deems Professor; Professor of Ophthalmology at CUIMC Chair, Department of Ophthalmology Takayuki Nagasaki, PhD Maria Luz Amaro-Quireza, OD Assistant Professor of Ophthalmic Science (in Ophthalmology) Instructor in Optometric Sciences (in Ophthalmology) at CUIMC at CUIMC Rando Allikmets, PhD Jeffrey Odel, MD William and Donna Acquavella Professor of Ophthalmic Science Professor of Ophthalmology at CUIMC (in Ophthalmology, and and Cell Biology) David Paik, MD James Auran, MD Associate Professor of Ophthalmic Science (in Ophthalmology) A Professor of Ophthalmology at CUIMC at CUIMC Srilaxmi Bearelly, MD, MHS Lisa Park, MD Assistant Professor of Ophthalmology at CUIMC Associate Professor of Ophthalmology at CUIMC Dana Blumberg, MD, MPH Konstantin Petrukhin, PhD Associate Professor of Ophthalmology at CUIMC Professor of Ophthalmic Science (in Ophthalmology) at CUIMC Steven Brooks, MD Lawrence Shapiro, PhD Anne S. Cohen Professor of Ophthalmology (in Pediatrics) Professor of Biochemistry and Molecular Biophysics; Professor G at CUIMC of Ophthalmic Science (in Ophthalmology) Daniel Casper, MD, PhD Suzanne Sherman, OD Professor of Ophthalmology at CUIMC Assistant Professor in Optometric Sciences (in Ophthalmology) at CUIMC Stanley Chang, MD K. K. Tse and Ku Teh Ying Professor of Ophthalmology Ronald Silverman, PhD Professor of Ophthalmic Science (in Ophthalmology) Royce Chen, MD Helen and Martin Kimmel Assistant Professor Janet Sparrow, PhD of Ophthalmology at CUIMC Anthony Donn Professor of Ophthalmic Science (in Ophthalmology, and Pathology and Cell Biology) D. Jackson Coleman, MD Professor of Ophthalmology at CUIMC Roslyn Stahl, MD Assistant Professor of Ophthalmology at CUIMC GCATCATT80ATTCGGTTACACGATCCAGAGTGCGGTAACCTTAACCTCAGAGTGAGTT CTATTTLoraC Glass,GG MDT AGCATCATTCTATTCGGTTTACACGGCGGTAACCTTAACA81CTCAGC Assistant Professor of Ophthalmology at CUIMC Leejee Suh, MD Miranda Wong Tang Associate Professor of Ophthalmology C. Gustavo De Moraes, MD, MPH, PhD at CUIMC Associate Professor of Ophthalmology Linus Sun, MD, PhD Peter Gouras, MD Instructor in (in Ophthalmology) Professor of Ophthalmology Gülgün Tezel, MD Vivienne Greenstein, PhD Professor of Ophthalmic Science (in Ophthalmology) Professor of Electrophysiology (in Ophthalmology) at CUIMC Tongalp Tezel, MD Noga Harizman, MD Chang Family Professor of Ophthalmology Associate Professor of Ophthalmology at CUIMC Andrei Tkatchenko, MD, PhD Lisa Hark, PhD, RD Associate Professor of Ophthalmic Science (in Ophthalmology, Professor of Ophthalmic Science (in Ophthalmology) at CUIMC and Pathology and Cell Biology) Donald Hood, PhD Danielle Trief, MD, MSc James F. Bender Professor of Psychology; Professor of Assistant Professor of Ophthalmology at CUIMC Ophthalmic Science (in Ophthalmology) Stephen Trokel, MD Jason Horowitz, MD C Professor of Ophthalmology at CUIMC Associate Professor of Ophthalmology at CUIMC Stephen Tsang, MD, PhD Simon John, PhD Laszlo T. Bito Professor of Ophthalmology, and Pathology Robert L. Burch III Professor of Ophthalmic Science and Cell Biology (in Ophthalmology) Tingting Yang, PhD Y. Shira Kresch, OD, MS Assistant Professor of Ophthalmic Science (in Ophthalmology) Instructor in Optometric Sciences (in Ophthalmology) at CUIMC Lauren Yeager, MD Jeffrey Liebmann, MD Assistant Professor of Clinical Ophthalmology Shirlee and Bernard Brown Professor of Ophthalmology T Xin Zhang, PhD Brian Marr, MD Jules and Doris Stein Research to Prevent Blindness Associate John Wilson Espy, MD Professor of Ophthalmology at CUIMC Professor; Associate Professor of Ophthalmic Science (in Carol Mason, PhD Ophthalmology, and Pathology and Cell Biology) Professor of Neuroscience; Professor of Pathology & Cell Biology; Professor of Ophthalmic Science (in Ophthalmology) DEPARTMENT STAFF

FULL-TIME CLINICAL FACULTY RESEARCH FACULTY BOARD OF ADVISORS CLINICAL PRACTICE LOCATIONS Rando Allikmets, PhD William Acquavella Srilaxmi Bearelly, MD, MHS* Flanzer Eye Center Comprehensive Ophthalmology Rand V. Araskog C. Gustavo De Moraes, MD, MPH, PhD* Edward S. Harkness Eye Institute G Debra Black James Auran, MD Peter Gouras, MD 635 West 165th Street Daniel Casper, MD, PhD Vivienne Greenstein, PhD Shirlee and Bernard Brown New York, NY 10032 Lisa Park, MD Lisa Hark, PhD, RD Robert L. Burch III Donald Hood, PhD Howard L. Clark, Jr. Gloria and Louis Flanzer Vision Care Center Simon John, PhD 880 Third Avenue Cornea & Refractive Surgery Carol Mason, PhD Joseph C. Connors New York, NY 10022 Leejee Suh, MD Irene Maumenee, MD Alan K. Docter Takayuki Nagasaki, PhD Danielle Trief, MD, MSc David Foley Robert Burch Family Eye Center David Paik, MD Stephen Trokel, MD Louis V. Gerstner, Jr. 250 West 64th Street Konstantin Petrukhin, PhD Lawrence Shapiro, PhD Arthur Hershaft New York, NY 10023 Glaucoma Ronald Silverman, PhD Leslie Hinton Stephen Ross Pediatric Eye Center Jeffrey Liebmann, MD Janet Sparrow, PhD Michael M. Kellen Linus Sun, MD, PhD* Morgan Stanley Children’s Hospital Dana Blumberg, MD, MPH Helen Kimmel Gülgün Tezel, MD 3959 Broadway, 5th Floor G.A. (Jack) Cioffi, MD Dr. Henry Kissinger Tongalp Tezel, MD* New York, NY 10032 C. Gustavo De Moraes, MD, MPH, PhD Andrei Tkatchenko, MD, PhD John Manice Noga Harizman, MD Stephen Tsang, MD, PhD* Polly Espy Millard Tingting Yang, PhD Roslyn Stahl, MD Cecilia Mullen Xin Zhang, PhD Bjørg and Stephen Ollendorff Neuro-Ophthalmology TEACHING FACULTY John Robinson Rajendra Bansal, MD Jeffrey Odel, MD Stephen Ross Alexandra Braunstein, MD Linus Sun, MD, PhD Robert Braunstein, MD Jean Sheng A C GCATCATT82ATTCGGTTACACGATCCARoyGA Cole,G TODGCGGTAACCTTAAJamesCC ShinnTCAGAGTGAGTT CTATTTC GGTAGCATCATTCTATTCGGTTT ACACGGCGGTAACCTTAACACTCAGC Oculoplastic and Reconstructive Hanna Coleman, MD Sir Howard Stringer Arthur Cotliar, MD Surgery Miranda Wong Tang Jeremy Cotliar, MD Lora Glass, MD Stephen Doro, MD Stanley Zabar Howard Eggers, MD Gregory Zaic Nancy Fan-Paul, MD, MPH and Contact Lens Design: hgDesign NYC George Florakis, MD Suzanne Sherman, OD Max Forbes, MD (Emeritus) Writing: Gina Shaw Maria Luz Amaro-Quireza, OD Pamela Gallin, MD Printing: The Standard Group Y. Shira Kresch, OD, MS Gennifer Greebel, MD Editors: George A. Cioffi, MD Thomas Flynn, MD Jeffrey M. Liebmann, MD Dan Jokl, MD Pediatric Ophthalmology Associate Editors: Steven Kane, MD, PhD Janet Sparrow, PhD Steven Brooks, MD Michael Kazim, MD Bonnie Wang Lauren Yeager, MD Hindola Lederman-Barotz, MD Jane Heffner Martin Lederman, MD Denisse Bejaran Francis L’Esperance, Jr., MD (Emeritus) Valerie Williams-Sanchez Retina and Vitreoretinal Surgery Martin Leib, MD Photography: Amelia Panico; Tongalp Tezel, MD Peter Libre, MD John Abbott; Iwan Baan; Jenny Srilaxmi Bearelly, MD, MHS Robert Lopez, MD Gorman; Chris Leary; Stanley Chang, MD Peter Maris, Jr., MD ©Nic Lehoux. Renzo Piano John Merriam, MD Building Workshop, Design Royce Chen, MD John Mitchell, MD Architect and Davis Brody D. Jackson Coleman, MD Rainer Mittl, MD Bond, Executive Architect Jason Horowitz, MD Golnaz Moazami, MD Special thanks to Stephen Tsang, MD, PhD Alan Morse, JD, PhD Ophthalmology Photography Hermann Schubert, MD and Imaging; Archives and Michael Weiss, MD, PhD Special Collections, Columbia Eric Wolf, MD University Health Sciences Lawrence Yanuzzi, MD Library * Also Clinical Faculty T A T Columbia University Irving Medical Center

Edward S. Harkness Eye Institute Vagelos College of Physicians & Surgeons Columbia University Irving Medical Center / NewYork-Presbyterian

635 West 165th Street New York, NY 10032-3797 columbiaeye.org GC