Foresight for Sight July 2021 Issue Number 2 / Volume 43

Retina Research Foundation Newsletter is published three times per year: Spring, Summer and Fall. The Audacious Goal of Regeneration Cells of the human retina are not replaced, so if brain through the optic nerve; 3) Müller glia cells they are damaged or degenerate, vision may be that support retina neuron structure and function and diminished or lost all together. The NIH/National may be reprogramed after other cell type injury. Eye Institute’s Audacious Goals Initiative (AGI) stimulates research dedicated to regenerating the RRF supports unique research opportunities light-sensitive retina and its connections to the brain, seeking to answer these same questions of retinal bold and daring work to be sure, and necessary regeneration, and often focuses on developing young ground work for reversing vision loss due to retina investigators as they collect the preliminary data degeneration. The initiative is driving therapeutic necessary to apply for funding by the NHI/NEI. RRF development from different perspectives, including also provides research funding to established vision noninvasive imaging to study the cells of the eye and scientists through nationally recognized awards response to therapies, regenerative factors discovery, such as the Award of Merit in Retina Research and promotion of innovative animal models for given in collaboration with the Retina Society. The testing therapies and bridge the gap between basic most recent recipient of the RRF Award of Merit research and human clinical trials. is Russell Van Gelder, MD, PhD, who researches retina regeneration and currently serves on the NEI’s The regenerative discovery projects explore five member AGI Steering Committee. opportunities within specific retinal cell types essential for sight: 1) photoreceptors, the light sensing cells In his award lecture given at the Retina Society’s annual of the retina; 2) retinal ganglion cells (RGCs) that meeting, “Prospects for Vision Restoration in Outer relay information from the photoreceptors to the Retinal Degeneration,” Dr. Van Gelder discussed

Bipolar RETINA CELL TYPES Muller Horizontal Cell photoreceptors Glia Cell Rod Amacrine Cell Cone Ganglion Cell RPE Vitreous Choroid

Copyright© LifeMap Sciences, Inc. - Discovery.lifemapsc.com (continued on page 2) (continued from page 1) 2020 the possibilities for restoring sight to people blinded by retinal degenerative RRF Award of Merit diseases such as age-related macular degeneration or . Recipient Dr. Van Gelder summarized the current approaches to vision restoration: stem cell replacement of damaged cells; electronic chips to simulate and transmit light receptivity to the brain; and light sensing protein (optogenetic) gene therapy, noting that all approaches face significant challenges to becoming established therapies. For gene therapy to successfully treat retinal degeneration, effective delivery methods must be developed to get the therapy to target retina cells, and because gene therapy is designed to change the functionality of how cells perform, significant consideration must be given to the implication that gene therapy patients may be precluded from receiving future, more effective therapies when they become available.

Replacing damaged retinal ganglion cells (RGCs) using precursor stem cells Russell Van Gelder, MD, PhD still remains beyond reach and as of now, no stem cell-based replacement Professor and Chairman treatment has received FDA approval. Audacious Goal Initiative researchers of the Department of Ophthalmology are trying different strategies including: using stem cells to grow RGCs that would then be transplanted to a patient’s retina, or recruiting other cell University of Washington types in a patient’s retina for reprogramming into RGCs, something some Seattle, WA amphibians and do naturally. Potential cell type candidates for reprogramming include retinal pigment epithelial (RPE) cells, Müller glia cells and amacrine cells. The key to unlocking these cell types already found in eye tissue as sources for RGC reprogramming is understanding the cues that direct their maturation and integration with other cells.

Dr. Van Gelder is pursuing a different approach to restoring retina function. His lab is investigating the therapeutic potential of synthetic small-molecule photoswitches for restoring light sensitivity to degenerated . Dr. Van Gelder is concentrating on determining how retinal ganglion cells can sense light and using these discoveries to treat blindness.

“The concept of restoring vision to someone who’s blind from retinitis pigmentosa, or from dry age-related macular degeneration, still falls into the category of miracle. We need to turn to science if we’re going to have the miracle of vision restoration for these patients become a reality” Russell Van Gelder, MD, PhD

Photoswitches are compounds that are chemically sensitive to light, and change to block voltage-gated potassium channels, which triggers depolarization of neurons and causes them to fire and send a signal. Dr. Van Gelder’s lab has studied three generations of these synthetic pharmacologic compounds with successive improvement and some do appear to work in animals. Dr. Van Gelder is hopeful about transition of this research to human clinical trials in the next several years.

2 Most Common Retinal Degenerative Diseases The most common retinal degenerative diseases are Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP). AMD causes the loss of central vision, while RP causes the loss of peripheral vision.

In AMD, build-up of toxic materials, age or environmentally caused degradation of cells, deteriorates the tissue adjacent to the retina called the retinal Normal vision Cataract Myopia pigment epithelium (RPE). The RPE provides essential support for retinal function. By 2050, the conservative estimate of the number of people with AMD in the U.S. is expected to be 5.4 million (NIH/NEI). Due to the aging of the U.S. population, Macular degeneration Glacoma some sources indicate prevalence will be up to four times larger.

Retinitis pigmentosa also causes damage to the RPE, which has a very limited ability to regenerate. Consequently, degeneration of Eye floaters Retinitis pigmentosa Total blindness these cells leads to photoreceptor The views of individuals with death and irreversible blindness. Retinitis pigmentosa is not prevalent and different vision anomalies considered rare, and it is generally estimated that this genetic disease affects (courtesy of NIH) one in 4,000 individuals in the U.S.

In many cases, individuals do not realize how serious the changes taking place in their vision are until irreversible damage has already occurred. Many eye diseases are asymptomatic in the early stages when treatment may prevent or delay disease onset, so early detection is extremely important. The early stages of both diseases are clinically evident, and these changes can be found during an annual visit to your ophthalmologist. If you do have the early stages of these diseases, your doctor will work with you to determine the best treatment, which may be complex and sometimes urgent.

Source: sciencedirect.com

3

Photo Selections

Photo Selections Researching Retina Regeneration With Assistance

RRF Grant Researcher From the Axolotl Dr. James Monaghan’s lab at Northeastern University in Boston, MA, might appear a little different from others supported by RRF because it is. Dr. Monaghan researches the complexJames tissueR. Monaghan, regeneration that PhD , salamanders Northeastern University, Boston, MA are capable of, including retinal regeneration. James R. Monaghan, PhD, Northeastern Humans cannot University, recover from Boston, MA retinal damage, but Mexican axolotl salamanders can regrow their entire retinas; in fact they are capable of regenerating complete appendages and other James R. Monaghan, PhD vital structures. Dr. Monaghan’s Northeastern University research seeks to understand Boston, MA the cellular and molecular mechanisms that enable these salamanders to replace damaged Photo by Matthew Photo by Matthew Modoono, Northeastern University or destroyed retinaPhoto tissues, by Matthew Modoono/Northeastern University knowledge essentialModoono/Northeastern for possible translation of University those mechanisms into future cures for degenerative diseases of the human retina.

With funding from RRF, Dr. Monaghan’s team has developed a technique that reveals cell types in the axolotl retina and their associated gene activity, useful for understanding the mechanisms behind regeneration at the molecular level. Preliminary data suggests that the may dictate what types of cells regrow in the new retina, and the research team confirmed that the regenerated retina re-establishes its connection with the brain, which is necessary for functionality. Additionally, Dr. Monaghan’s research documented the new discovery that the axolotl retina contains a type of glial cell that may serve as a stem cell during salamander retinal regeneration. The Axolotl, a feathery-gilled­ Mexican salamander Currently, Dr. Monaghan is investigating how Notch signaling controls The Axolotl, a feathery-­‐gilled (alternative photo retina cell regrowth after an injuryThe and how Axolotl, the newly a feathery discovered-­‐gilled stem cells (alternative photo Mexican salamander drive regenerationoption of the for retina. the By learning axolotl) which elements enable axolotl cells to behave this way, perhapsMexican those elements salamander may be applied to human option for the axolotl) stem cell therapy and retinal regeneration in the future.

What is Notch signaling? Notch signaling occurs in all animal species and promotes neural cell differentiation. It plays a major role in the regulation of embryonic development. The Notch signaling pathway is a cell signaling system that has remained relatively unchanged across various biological species. Cell signaling is the ability of a cell to receive, process, and transmit signals internally and externally across cell membranes in its environment. Notch signaling promotes the rapid increase of signaling during neurogenesis, the process by which nervous system cells, neurons, are produced by their precursor neural stem cells (NSCs).

4 Article # 4 Article Yale Scientists # 4 Find Dozens of Genes That Block Nerve YaleCell Scientistsegeneration R Find Dozens Of GenesYale That Scientists Block Nerve Find Dozens of Genes That Block Nerve CellIn Regeneration an extensive effort of screening 400 mouse genes, Yale School of Medicine researchers have identified 40 By screeninggenes 400 mouse actively genes, Yale School involved of Medicine researchers in suppression have of axon regeneration in central nervous system cells. By editing out one identifiedCell 40 genes activelyegeneration R involved in suppressing the regeneration of the axon, theof long those nerve fiber in central genes, nervous they system cells. were By able to restore editing out axons in ocular nerves of mice damaged by glaucoma. one of those genes, they were able to restore axons in ocular nerves of mice damagedIn by an glaucoma. extensive effort of screening 400 mouse genes, Yale School of Medicine researchers have identified 40

The abilitygenes to silence actively gene involved in suppression of axon regeneration in central nervous system cells. By editing out one expressionof using those RNA techniques genes, they were able to restore axons in ocular nerves of mice damaged by glaucoma. combined with new gene editing technologies capable of removing single genes to gauge their functional impact

has allowed researchers to Untreated greatly expand their search for Ocular Nerve genes involved in suppressing regrowth of neurons.

Interleukin-22, one of the 40 Directionally, light signals move from the eye through the axon genes studied is responsible (part of the optic nerve) connecting to the brain for producing an immune system regulator. Elimination of this immune mediator altered the expression of many neuronal regeneration genes and greatly increased axon regeneration in mouse models

1122 of glaucoma. Future research will exploreDirectionally, how modifying light signals move rom f the e ye through the axon (part of the optic nerve shown above ) connecting to the b rain or blocking those 40 genes might affectAxons the repair extending of from the eye (left side of photos) to the brain (right side of photos) in the optic neurons damaged by stroke and traumaticnerve brain and after spinal the Axons extending nerve from the has eye (left side been of photos) crushed. to the brain (right In side of the control, untreated case (top photo) very few nerve cord injuries.Directionally, light signals photos) move in therom f opticthe nervee ye after through the nerve thehas axon been (part crushed. of In the the optic control, nerve shown above ) connecting to the b rain fibers succeed untreated in case growing (top photo), very back. few nerve fibers After succeed suppression in growing of Interlukin-­‐back.22 (Il22) in the retina, many more The researchaxons was funded can in regenerate After suppression of Interlukin-22 from the injury (bottom (Il22) in the retina, phot o)many. more (Image: axons can Strittmatter lab, Yale) Axons extending regenerate from from the injury the (bottom eye (left side photo). of photos (Image:) Strittmatter to lab, the Yale) brain (right side of photos) in the optic part by National Eye Institute’s Audaciousnerve Goals Initiative. after the nerve has been crushed. In the control, untreated case (top photo) very few nerve fibers succeed in growing back. After suppression of Interlukin-­‐22 (Il22) in the retina, many more Source: news.yale.edu In axons recent can decades regenerate , scientists from have the injury (bottom found phot o) a . (Image: handful Strittmatter of genes lab, Yale) involved in suppressing regeneration of central Retinanervous Research Foundation system is dedicated cells. to However, the eradication of retina the disease ability through programs to in research silence and education. gene expression using RNA techniques and new gene 1977edi Butlerting Boulevard technologies • Houston, Texas 77030 • (713) capable 797-1925 • [email protected] of removing • retinaresearchfnd.org single genes and gauging their functional impact have allowed 5 In researchers recent to decades, scientists greatly have expand found their a search for other culpable handful genes of . genes involved in suppressing regeneration of central nervous system cells. However, the ability to silence gene expression using RNA techniques and new gene ediInterleukinting technologies -­‐22, ne o of capable the 40 of genes removing edited out, encodes single for an genes and gauging their immune functional system impact regulator. have allowed Elimination of this researchers immune mediator to greatly altered expand the their expression search for other culpable of many genes. neuronal regeneration genes and greatly increased axon regeneration in mouse models of glaucoma, they found. Future research will explore how modifying or Interleukinblocking -­‐ those 22, ne o 40 of genes the 40 might genes affect edited out, encodes the for repair an immune of neurons system damaged regulator. by Elimination stroke of this and traumatic brain spinal immune cord injuries. mediator altered the expression of many neuronal regeneration genes and greatly increased axon regeneration in mouse models of glaucoma, they found. Future research will explore how modifying or blocking The research those was 40 funded in genes part by National might affect Eye Institute’s the Audacious repair of Goals neurons Initiative. (Word damaged count: 18 by 6) stroke and traumatic brain spinal cord injuries. Source: news.yale.edu The research was funded in part by National Eye Institute’s Audacious Goals Initiative. (Word count: 186)

Source: news.yale.edu

Article # 5

Katharine W. Orton Joins RRF Board of Directors

In April 2021, Kathy Orton became the newest member of the RRF Board of Directors. Her interest in the work of the Foundation spans 30 years from when she agreed to first serve as an RRF Advisory Trustee and intersects with her professional experience in finance and her dedication to the cultural and health care institutions of Houston.

Mrs. Orton’s ties to the Houston health care community are deep-rooted, reaching back to her time as Chairman and CEO of Texas Commerce Medical Bank, which was an acknowledged leader specializing in financing for medical professionals and institutions in the Texas Medical Center. Later, as a Managing Director at JPMorgan Chase, she originated and managed a multi-billion dollar portfolio of credit facilities that provided tax exempt financing to government and not for profit entities. Up until her recent retirement, Mrs. Orton was a Senior Vice President and Regional Manager of the Wells Fargo Healthcare Financial Services Group, working with clients throughout Texas, Colorado, Oklahoma, Louisiana and Arkansas.

Mrs. Orton is a highly respected leader serving our city in many capacities. In addition to RRF, she is on the Alley Theatre Board of Directors, a member of the Development Board of The University of Texas Health Science Center, and active with the United Way and the Museum of Fine Arts, Houston. She has previously volunteered her expertise and time as a board member with numerous other Houston health care, arts, and charitable organizations.

A sports enthusiast, Kathy enjoys the occasional break from the local heat and humidity and gets away to spend time in the mountains of Colorado where she, her husband, John, and their two grown daughters pursue many of their favorite outdoor activities including skiing, golfing, andKatharine hiking. W. Orton Joins(word count RRF 287) Board of Directors

In April 2021, Kathy Orton became the newest member of the RRF Board of Directors. Her interest in the work of the Foundation spans 30 years from when she agreed to first serve as Article # 5 an RRF Advisory Trustee and intersects with her professional experience in finance and Katharine W. Orton Joins RRFher Boarddedication of Directors to the cultural and health care institutions of Houston. In April 2021, Kathy Orton became the newest member of the RRF Board of Directors. Her interest in the work of the Foundation spans 30 years from when she agreed to first serve as an RRF Advisory Trustee and intersectsMrs. withOrton’s her professionalties to the experience Houston inhealth finance care and her dedication to the cultural and healthcommunity care institutions are deep-rooted, of Houston. reaching back to her time as Chairman and CEO of Texas Commerce Mrs. Orton’s ties to the HoustonMedical health care Bank, commu whichnity are was deep an-rooted, acknowledged reaching back to her

Kathytime as Orton Chairman and CEO of Texasleader Commerce specializing Medical in Bank, financing which was for an acknowledgedmedical leader specializing in financing for medical professionals and institutions in the Texas Medical professionals and institutions in the Texas Medical Center. Later, as a PhotoCenter. credit: Later, Houston as a Managing Chronicle/Gary Director Fountain at JPMorgan Chase, sheKathy originated and and John managed Orton a Managingmulti-billion Directordollar portfolio at JPMorgan of credit facilitiesChase, shethat originatedprovided tax and exempt managed financing a multi- to government billionand not dollarfor profit portfolio entities. of Up credit until herfacilities recent thatretirement, provided Mrs. tax Orton exempt was afinancing Senior Vice President andto Regional government Manager and of notthe Wells for profit Fargo Healthcareentities. Financial Up until Services her recentGroup, working with clientsretirement, throughout Mrs. Texas,Orton wasColorado, a Senior Oklahoma, Vice President Louisiana and and Regional Arkansas. Manager of the Wells Fargo Healthcare Financial Services Group, Mrs. Orton is aworking highly respected with clients leader throughout serving our cityTexas, in many Colorado, capacities. Oklahoma, In addition to RRF, she is on the AlleyLouisiana Theatre and Board Arkansas. of Directors, a member of the Development Board of The University of Texas Health Science Center, and active with the United Way and the Museum of Fine Arts, Houston. She has previously volunteered her expertise and time as a board member with numerousMrs. other Orton Houston is a health highly care, respected arts, and leader charitable serving organizations. our city in many capacities. In addition to RRF, she is on the Alley Theatre A sports enthusiast,Board Kathy of Directors, enjoys the a occasional member breakof the from Development the local heat Board and humidity of and gets away to spendThe University time in the mountains of Texas of Health Colorado Science where she,Center, her husband and active, John, and their two grown daughterswith the pursue United many Way of theirand favoritethe Museum outdoor of activities Fine Arts, including Houston. skiing, golfing, and hiking. She has previously volunteered her expertise and time as a board member with numerous other Houston health care, arts and charitable (word count 287) organizations.

A sports enthusiast, Kathy enjoys the occasional break from the local heat and humidity and gets away to spend time in the mountains of Colorado where she, her husband, John, and their two grown daughters pursue many of their favorite outdoor activities, including skiing, golfing and hiking.

John and Kathy Orton

Photo credit: Houston Chronicle/Gary Fountain Kathy and John Orton 6 It’s Summer, Are Your Eyes Protected? Years of chronic sunlight exposure can increase the risk of developing a cataract, a clouding of the eye lens that typically occurs with aging. Similarly, studies funded in part by the NEI, link ultra-violet (UV) sun light damage to a process called oxidative stress that hastens retinal degeneration. The Spectrum of While major studies show no conclusive evidence that overexposure to the Visible and Non-Visible sun directly causes macular degeneration, some findings suggest at least an association between AMD and cumulative eye damage from overexposure to Light both UV and high energy visible (HEV) or “blue” light.

Most of your exposure to blue light occurs when you’re outside during the day because sunlight is the main source of blue light. There are additional NON-VISIBLE VISIBLE artificial sources of blue light as well — including computer and phone screens, BLUE LIGHT and fluorescent and LED lights. UV (HEV)

HARMFUL LIGHT BENEFICIAL LIGHT The cornea and lens of the eye are (UV) (BLUE-VIOLET) (BLUE-TURQUOISE) (REST OF VISIBLE LIGHT) effective at blocking UV rays from reaching the light-sensitive retina at the back of the eyeball. But virtually 100% of blue light passes through these structures and reaches the retina. In animal laboratory studies, blue light has been shown to be harmful to light- sensitive cells like those in the retina. The damage resembles that caused by macular degeneration, which can lead to permanent vision loss. More research is needed to determine how much blue light from sunlight and digital devices is “too much” blue light for the retina. This summer, stay on the safe-side and always wear UV protective sunglasses when you are outdoors, and when you are indoors and looking at a device screen, consider wearing computer glasses to filter out blue light. Remember, it is cumulative exposure to UV and blue light that is possibly detrimental to retina tissues. Source: NEI, optomerytimes.com

7 FREE MATTER FOR THE BLIND OR 1977 Butler Boulevard, Houston, Texas 77030 HANDICAPPED (713) 797-1925 • [email protected] Editor in Chief: Alice McPherson, MD Managing Editor: Virginia Gissel Schwanauer Retina Research Foundation is a Nonprofit Organization. retinaresearchfnd.org

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Special Remembrances ESTATE GIFTS IN MEMORY OF The Estate of Margaret F. Barrow Rhett Butler The Estate of Marcella D. Mangiaracina Mr. and Mrs. Chris D. Mantzuranis L. Henry Gissel, Jr. Rhett Butler Trust Mr. and Mrs. Lewis H. Gissel, III Cherald E. Williams Estate Walter O’Neil Jimmie Jordan Jacquelyn M. Royce Bettie H. Lee

A GIFT TO RRF CAN SAVE SIGHT Retina Research Foundation, a public foundation, supports research directed toward treating, preventing or curing all retinal diseases that damage and destroy vision. Your support is vital to the success of our efforts. RRF accepts secure donations at retinaresearchfnd.org. You can support RRF by making your online purchases through . Use the link on RRF’s website or go to smile.amazon.com to register. Select RRF as your charity of choice. Once selected, all future purchases will result in an automatic donation to RRF of 0.5% of your purchases, at no cost to you. RRF is a registered 501(c)(3) non profit with these organizations: Benevity, Network for Good and YourCause. Thank you!

ALL GIFTS AND BEQUESTS ARE TAX DEDUCTIBLE. RRF is recognized by the U.S. Internal Revenue Service as a publicly supported tax exempt organization under section 501(c)(3) of the Internal Revenue Code.

RRF accepts secure donations at retinaresearchfnd.org • For more information call: 713-797-1925.