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52 N O V E M B E R 2 0 Retinal alfred t. kamajian t. alfred 52 november 2012 From inherited retinal dystrophies to AMD, the pace of gene therapy is picking up, spurred on by recent success with Leber congenital amaurosis. An update on current research and insights Gene Therapyfrom leaders in the field. BY ANNIE STUART, CONTRIBUTING WRITER fter a few false starts in early gene therapy clinical That’s a far cry from evaluating gene therapy for liver trials in the 1990s, the dramatic success of the Leber disease, for example, where it’s not possible to make direct congenital amaurosis (LCA) trials has spurred re- observations. A newed interest and a great deal of development in the field at large. Although research is progressing in uveitis, Retinal Rewards glaucoma, and cornea, the most promising results in oph- The retina is a desirable target for gene therapy, largely thalmology thus far have emerged with retinal disorders. because it is an essential, irreplaceable part of the central As with so many areas of study, the eye offers a unique nervous system, said Richard A. Lewis, MD, professor of opportunity for gene therapy. “Because of its size, the eye ophthalmology and molecular and human genetics at Bay- requires relatively small doses to achieve a therapeutic ef- lor College of Medicine in Houston. “You can change some fect,” said J. Timothy Stout, MD, PhD, MBA, genetic re- things about the anterior segment of the eye—repair cor- searcher and professor of ophthalmology at Oregon Health neal damage, do transplants, or remove cataracts—but you & Science University in Portland. This was particularly can’t replace the retina.” advantageous at the very earliest stages of eye gene therapy, From inherited retinal dystrophies to AMD, gene therapy he said, when making large amounts of gene vectors was no offers promise for the clinician in two primary ways: “There easy task. Small doses and localized treatment also translate are a number of retinal diseases for which there are zero into lower risks of systemic toxicity. And the contralateral therapeutic options,” Dr. Stout said, “and a number for eye provides a convenient control.1 which we have therapeutic options, but the delivery of the The eye is also anatomically isolated, immune privileged, therapies is either ineffective or cumbersome.” For example, and easily accessible. By surveying its landscape with high- he said, sustained genetic expression in the retina might ob- resolution imaging, genetic researchers can see the results of viate the need for repeated treatments such as injections of the viral vector injections noninvasively and within a matter biologics for AMD, thereby lessening the risks of local side of minutes, said Dr. Stout. effects including infection or retinal detachment. eyenet 53 Vector Variables and Surgical Scenarios Although these vectors transduce retinal pigment Manipulated to become virtually benign, viral vec- epithelium (RPE) cells very efficiently, they are less tors are the space shuttles of gene therapy. With a efficient than AAV vectors at transducing photore- range of cargo capacity, stability of expression, im- ceptor cells. munogenicity, and differential targeting of cells, Unlike AAVs (and AVs, below), which are basi- three main types of vector have been used for retinal cally inert delivery systems, lentiviruses function by gene therapy: adeno-associated virus (AAV), lenti- incorporating themselves into cells, said Dr. Lewis. virus, and adenovirus (AV).1 However, no gene therapy trial with a retrovirus Tailored usage. “As with a toolbox of antibiotics, has ever gone forward without proof that the virus we use different vectors for different purposes,” said is replication negative, said Stephen M. Rose, PhD, Dr. Stout, reflecting on the tremendous progress chief research officer for the Foundation Fighting made since his graduate-school days, when he and Blindness in Columbia, Md. colleagues were first tackling a prerequisite to thera- AV vectors. Used more commonly in the past, AV peutic gene delivery—figuring out how to make vectors elicit expression for only about 90 days, said viruses capable of transferring genetic information Dr. Stout. “However, there might be clinical scenar- into cells. ios where turning off or modulating something for Today, however, the world of vectorology is ac- a brief period of time celerating quickly, said Jean Bennett, MD, PhD, might be just fine.” professor of ophthalmology at the University of Nonviral delivery. Al- Pennsylvania in Philadelphia and scientific direc- though they aren’t quite tor for phase 1/2 human LCA clinical trials. “People ready for prime time, are developing multiple serotypes—‘flavors’ of the nonviral vectors carry reagent—with different attributes, some of which great promise, said may be beneficial for particular diseases,” she said. Dr. Bennett. Whereas However, each new vector requires detailed safety lentiviruses top out studies to determine whether it goes outside a target at 8,000 or 9,000 base area, attaches to the wrong cell type(s), or induces an pairs, these lipid- and immune response, for example. nanoparticle-based vec- Cross-section of a AAV vectors. Used in LCA trials, AAV vectors have tors have no limitation mouse eye following proved to be remarkably safe, said Dr. Stout, and in packaging capacity, subretinal injection of they can express the contained genes for long periods she said. “Most use a AAV carrying the green of time. “We think that patients we’re treating for trick to compact the fluorescent protein gene. LCA may well be cured, because they’re going to be DNA or RNA to al- Efficient gene delivery making RPE65 protein for the long haul.” low it to transfer across can be achieved, target- AAV vectors transduce cells efficiently, added the lipid bilayer of cell ing almost 100 percent James W. Bainbridge, MA, PhD, FRCOphth, pro- membranes,” she said. of the photoreceptor and fessor of retinal studies at the University College They also don’t carry RPE cells. London Institute of Ophthalmology. “Now there is viral proteins with the a wide range of serotypes that can allow a range of potential to induce an immune response, she added. cell targeting,” he said, adding that one disadvantage However, they may lack the staying power of some of AAV is its relatively small capacity, viral vectors.2 Gene delivery using the which can pose a problem with larger Surgical approaches. Given the vectors currently AAV 2/8 vector restores genes, such as the gene involved in in use, retinal gene delivery now involves a standard expression of AIPL1, a Stargardt disease. vitrectomy and subretinal injections, said Dr. Stout. protein missing in a mod- Lentiviral vectors. By contrast, said “But that may not be the way we deliver therapeutic el of severe early-onset Dr. Bainbridge, large carrying capacity material forever. People are working on modifying retinal degeneration. is an advantage of lentiviral vectors. the capsid proteins of the AAV,” said Dr. Stout, which may allow it to transduce the same cells using intra- vitreal injections. Additionally, researchers are investigating less invasive surgical approaches, such as gaining access to the retina and RPE through the suprachoroidal space. This involves making a small cut in the sclera and threading a cannula along the wall of the eye to the back of the eye. “We have good data to suggest we’ve obtained transduction of the photoreceptors for centre research biomedical research health for institute national ophthalmology moorfields university and at college london 54 november 2012 and the blood vessels,” said Dr. Stout.3 Such less in- it affects their vision. vasive approaches, which preserve the integrity of the We’ve got some kids retina, are particularly important in certain circum- who clearly see better stances, said Dr. Rose. “In cases like retinoschisis, in the treated than in where your retina looks like Swiss cheese, you really the untreated eye,” he don’t want to disturb what’s there.” added, describing chil- dren who can now ride LCA Lessons—and a Caution bikes or navigate better Beginning in 2008, independent studies of patients in the dark, thanks to affected with LCA due to mutations in the RPE65 improved photorecep- gene were published by researchers in London, Phila- tor function. In others, delphia, and Florida. At the time, it was known that their nystagmus has the RPE65 protein played a “recycling role” in the resolved. visual pathway and that a subset of LCA patients did Further studies have not make this protein. However, it wasn’t known shown additional benefits of treat- Extramacular subretinal whether the simple act of supplying a patient with a ing the second eye, said Dr. Bennett. bleb (shaded area) in normal copy of the gene would slow or reverse the However, she noted that LCA trials patient with LCA. disease. “Getting normal copies into enough RPE have highlighted the need for more cells slowed down degeneration in the dog model, clearly defined outcome measures, beyond eye charts and, as it turns out, this works remarkably in hu- and visual fields, for patients receiving gene therapy. mans,” Dr. Lewis said. “These tests either are not useful or have limited util- “The LCA studies demonstrated proof of principle ity for many diseases. There are other features of vi- for a technique that could be widely applicable to a sion that are clinically meaningful, such as the abil- number of inherited retinal conditions, particularly ity to see in dim light or to navigate independently.” those in which a single gene is responsible for lack of Timing. The LCA trials appear to show that the function of an essential protein in the retina,” said earlier the treatment, the better the outcome, said Dr. Bainbridge. Dr. Stout, who added that this may not hold for all Safety. “The primary message from the LCA trials diseases and for all forms of gene therapy.
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