Foundation Fighting Blindness Commits $6.5 Million for New Retinal Disease Research Grants
New grants include development of CRISPR/Cas9 gene-editing treatments, new disease models, and a retinal regeneration therapy
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COLUMBIA, Maryland – August 21, 2020 – The Foundation Fighting Blindness, the world’s leading organization committed to finding treatments and cures for blinding retinal diseases, has announced $6.5 million in funding for 15 new grants, bringing its research portfolio to a total of 84 grants. The projects were selected from 134 proposal submissions made by investigators in fall 2019. The submissions were rigorously evaluated and scored by the Foundation’s Scientific Advisory Board, which is comprised of the world’s top retinal disease experts.
“First and foremost, we are committed to projects that will lead to vision-saving treatments and cures,” says Benjamin Yerxa, PhD, chief executive officer at the Foundation. “Our funding strategy also focuses on critical research gaps, that when addressed, will move the whole field forward in a significant way. For example, the grants for new models for RP, Usher syndrome type 1B, and Stargardt disease will have a major impact on therapy development. Proof-of-concept for a therapy in a model that closely replicates human disease can be the springboard for clinical trials.”
First and foremost, we are committed to projects that will lead to vision-saving treatments and cures. Our funding strategy also focuses on critical research gaps, that when addressed, will move the whole field forward in a significant way.
Tom Reh, PhD, a retinal regeneration expert at the University of Washington, is receiving a new Foundation grant to continue his innovative research in a treatment that empowers the retina for self-regeneration. While most regenerative retinal therapies involve transplantation of new retinal cells derived from stem cells, Dr. Reh’s approach would enable a diseased retina to grow its own new photoreceptors, the cells that make vision possible.
“The immediate goal is to find out whether we can stimulate regeneration of new neurons in human retina from the Muller glia using the same factors that work in mice,” says Dr. Reh. “If we are successful, I imagine a day when an ophthalmologist will give injections of a gene or two into a late stage patient over a period of a few weeks and this will set in motion a process of remaking the cone photoreceptor cells in the fovea and restoring some vision to that person.”
Dr. Reh received the Foundation’s Board of Director’s Award in 2010 for his breakthroughs in retinal regeneration.
Summaries of Other Newly Funded Grants
Homology-Independent Genome Editing for Treatment of Stargardt Disease
Ivana Trapani, PhD, Università degli Studi di Napoli “Federico II” Naples, Italy
Gene therapy development for Stargardt disease is challenging because ABCA4, the mutated gene causing Stargardt disease, is too large for most viral delivery systems. Dr. Trapani is evaluating a highly efficient CRISPR/Cas9 gene-editing technology — homology independent targeted insertion (HITI) — to address mutations in ABCA4. Her early proof-of-concept studies are being performed in a Stargardt disease mouse model and a three-dimensional retinal organoid in a dish.
ADAR-Based RNA Editing as a Potential Therapy for Inherited Retinal Degenerations
Dror Sharon, PhD, Hadassah-Hebrew University Medical Center
Many emerging therapies target mutations in our genes — our DNA. Dr. Sharon is investigating a new tool for editing RNA — the genetic messages derived from DNA which are used by our cells to produce proteins. Known as “intrinsic adenosine deaminase acting on RNA,” or ADAR, the technology specifically addresses G-to-A mutations. Dr. Sharon believes that about 30 percent of the most commonly reported IRD-causing mutations can be targeted for ADAR editing (mainly in relatively large genes such as ABCA4 and USH2A). His lab is evaluating the technology in cells and mouse models of retinal disease.
Prime Editing for Usher Syndrome Type 2A
Bence Gyorgy, MD, PhD, Institute of Molecular and Clinical Ophthalmology Basel
Dr. Gyorgy is developing a gene correction strategy known as prime editing, a novel technology that is in some ways similar to gene editing with CRISPR/Cas9, but potentially more precise and efficient. Instead of cutting the double strands of DNA, it nicks the DNA, which may be a preferred approach to correcting single-letter mutations. Dr. Gyorgy is developing a prime editing treatment to insert the missing G nucleotide into retinal cells with the relatively common USH2A mutation del2299G. In order to facilitate translation of this concept to the clinic, he will evaluate the therapy in human retinal explants, human engineered retinal organoids and humanized mouse models. If the approach is successful, it may be applied to other mutations and IRDs.
Creation of New Models of Inherited Retinal Disease in Pigs
Maureen McCall, PhD, University of Louisville
Though rodents are often used as models for inherited retinal diseases (IRDs), they are limited in recapitulating human IRDs because they don’t have cones, the retinal cells that enable humans to perceive details and colors, and see in lighted settings. Pigs do have cones and are easy to engineer to model IRDs in humans. Dr. McCall is creating a slow degeneration pig model of RP (RHO-P23H) as well as a pig model of Stargardt disease. The models will be useful for evaluating emerging therapies in preparation for clinical trials.
Generation and Characterization of a Pig Model of Retinitis Pigmentosa (EYS mutation)
Hemant Khanna, PhD, University of Massachusetts Medical School
Mutations in the EYS gene are the second most common cause of autosomal recessive RP in humans. However, the intact EYS gene is absent and/or disrupted in many animals, including mice and rats. The gene is present in pigs, so Dr. Khanna and his colleagues are developing a pig model of EYS-associated RP, which will be useful in understanding the effects of EYS mutations and testing emerging EYS therapies.
Large Animal Model of Usher Syndrome Type 1B
Martha Neuringer, PhD, Oregon Health & Science University
One of the biggest challenges in developing therapies for the vision loss caused by Usher syndrome is that the existing animal models (namely rodents) for the condition don’t have vision loss. Using gene-editing techniques, Dr. Neuringer and her colleagues are developing a large animal model of Usher syndrome type 1B, which is caused by mutations in the gene MYO7A. She is characterizing the resulting syndrome from birth onward, including changes in the retina and auditory system. She will also perform an initial test of the feasibility of using this model to evaluate dual-vector gene therapy to maintain retinal function and vision. In a separate grant, the Foundation is funding Shannon Boye, PhD, University of Florida, to develop a dual-vector MYO7A gene therapy for Usher 1B.
Developing a Large Animal Model of Stargardt Disease
Botond Roska, MD, PhD, Institute of Molecular and Clinical Ophthalmology Basel
Stargardt disease affects the fovea, the central part of the retina that is responsible for high visual acuity. However, rodents don’t have foveae so they don’t serve as good models for Stargardt disease. Dr. Roska is developing a Stargardt disease model in marmosets, which do have foveae. His model will have the mutation c.5882 G>A (p.G1961E) in ABCA4 — a mutation that affects 15-20 percent of humans with Stargardt disease. The model will contribute to understanding the disease mechanisms and help researchers to evaluate not only small molecules but also precision gene editing tools to restore affected ABCA4 protein function.
Penn Large Animal Translational and Research Center
William Beltran, VMD, PhD, School of Veterinary Medicine-University of Pennsylvania
The PENN Large Animal Model Translational and Research Center plays a critical role in bridging basic science and the testing of new therapies in clinically relevant canine models by supporting the research conducted by inherited retinal disease (IRD) investigators affiliated with the facility and Foundation Fighting Blindness-sponsored scientists from other institutions. The grant is focusing on therapy development and evaluation of canine models for a number of IRDs and will include studies to prepare for clinical trials for Best disease and retinitis pigmentosa (RP) gene therapies.
Advancement of Ellipsoid Zone Intensity as a Surrogate Biomarker for Photoreceptor Structure
Joseph Carroll, PhD, Medical College of Wisconsin
Dr. Carroll and his team are using optical coherence tomography (OCT) to develop and improve validated markers of retinal structure, including the ellipsoid zone (EZ), band which correlates with the population of healthy photoreceptors in patients’ retinas. The investigators are studying EZ band reflectivity as a marker for photoreceptor health. Validated markers developed in the study will enable clinical researchers to more effectively evaluate emerging therapies in clinical trials for a number of conditions including: retinitis pigmentosa, Stargardt disease, achromatopsia, and choroideremia.
Assessing the Function of Individual Cells in Patients with Inherited Retinal Diseases
Robert Cooper, PhD, Marquette University
Ophthalmoscopes are the devices that eye doctors use to examine patients’ retinas during office visits. Dr. Cooper is developing a highly sensitive ophthalmoscope, which incorporates adaptive optics, to visualize retinas at the cellular level. Determining the rate of disease progression often requires years of clinical examination. Even then, changes in disease presentation are often subtle and difficult to reliably assess. By developing a more sensitive ophthalmoscope for measuring disease progression, eye doctors can provide patients with more timely and precise assessments of their retinal health.
Scrutinizing Protein Complex Assembly in Photoreceptor Connecting Cilia
Ronald Roepman, PhD, Radboud University Medical Center
Photoreceptors, the long sensory cells that make vision possible, are comprised of two primary parts: the outer segment, which senses light, and the inner segment, which produces the proteins that are shuttled into the outer segment so that the photoreceptor processes light. A small channel between the inner and outer segment is called the connecting cilium and is often a bottleneck for protein assembly and trafficking in retinal diseases such as Leber congenital amaurosis, Usher syndrome, Bardet Biedl syndrome, and retinitis pigmentosa. Dr. Roepman will be creating a “retina in a dish” to recreate/model the bottleneck and investigate ways to overcome it to save vision.
2020 Diana Davis Spencer Clinical Research Fellowship Awards
Ocular Perfusion in Retinal Degeneration
Giacomo Calzetti, MD, Institute of Molecular and Clinical Ophthalmology Basel
Research to date has not determined the contribution of retinal blood flow to degeneration in retinal diseases. Dr. Calzetti is developing new imaging techniques and methods to assess blood flow in USH2A and ABCA4 patients to facilitate deeper understanding of the pathophysiology of inherited retinal diseases.
Characterization of Biomarkers for Cystoid Macular Edema in Retinitis Pigmentosa
Cristy Ku, MD, PhD, Oregon Health & Science University
Current treatment options for cystoid macular edema in retinitis pigmentosa (RP-CME) are limited. Dr. Ku is investigating the mechanisms behind RP-CME through analyzing biomarkers of inflammation in the aqueous humor and plasma in patients with RP-CME. Dr. Ku’s research seeks to improve the clinical management of RP-CME by identifying novel therapeutic targets.
Optimizing Gene Therapy for Choroideremia: Redefining Cellular Targets, Treatment Windows and Outcome Measures
Erin O’Neil, MD, University of Pennsylvania
Ongoing clinical trials to assess gene therapy for choroideremia have shown modest effectiveness. Dr. O’Neil is exploring additional retinal cell targets that may improve gene therapy outcomes. Additionally, she will study the early natural history of choroideremia to identify the best time to intervene with gene therapy early in disease.
About the Foundation Fighting Blindness
Established in 1971, the Foundation Fighting Blindness is the world’s leading private funding source for retinal degenerative disease research. The Foundation has raised more than $760 million toward its mission of accelerating research for preventing, treating, and curing blindness caused by the entire spectrum of retinal degenerative diseases including: retinitis pigmentosa, age-related macular degeneration, Usher syndrome, and Stargardt disease. Visit FightingBlindness.org for more information.