Foundation Commits More Than $15 Million to 23 Promising Research Projects for Eradicating Retinal Diseases
Eye On the Cure Research News
Funding for the new grants was made possible by Foundation’s strong donor base and philanthropic partners
The Foundation Fighting Blindness added 23 new research projects to its portfolio, an investment totaling more than $15 million, during its Fiscal Year 2022 (ending June 30, 2022). Project awards ranged from early-stage lab research to identify treatment targets to translational efforts for advancing emerging therapies toward clinical trials.
Examples of FY2022 grants include:
- Empowering the degenerating retina to self-regenerate (sprout new photoreceptors) in mammals.
- Advancing several gene-agnostic treatment approaches for preserving vision.
- Developing new models for USH1B (MYO7A), USH2A, CRB1, PRPF31, EYS, and ABCA4 (Stargardt disease) to better understand disease mechanisms and test potential therapies.
Research grants were selected after a rigorous review process conducted by the Foundation’s Scientific Advisory Board, which is comprised of more than 60 of the world’s leading retinal scientists and clinicians.
The Foundation’s current research portfolio funds a total of 84 projects.
“There is something for everyone with these new investments. The new grants include gene-targeted and gene-agnostic approaches to address the entire spectrum of retinal degenerations that affect people of all ages and backgrounds around the world,” said Claire Gelfman, PhD, chief scientific officer at the Foundation. “We greatly appreciate the generosity and commitment of our passionate donor base and funding partners, including the Diana Davis Spencer Foundation, the Free Family Foundation, and Save Sight Now. Ultimately, it’s patients, families, and philanthropic groups that drive this outstanding research.”
Translational Research Acceleration Program (TRAP Awards)
“Retinal regeneration through an epigenetic therapy”
Rui Chen, PhD
Baylor College of Medicine
Some species, such as zebrafish and amphibians, have a remarkable ability to repair damaged retina tissue through self-regeneration. Dr. Chen is developing a novel approach to activate retinal Müller glial cell reprogramming through epigenetic manipulation in order to generate new photoreceptor cells. This would serve as an alternative to cell transplantation therapy by reprogramming endogenous cells in the mammalian retina to induce neural (photoreceptor) regeneration.
“Towards the clinical translation of mutation-independent treatment for hereditary retinal degeneration”
Vision loss for many people with RP and other inherited retinal degenerations is caused by the accumulation of a molecule called cyclic guanosine monophosphate (cGMP). While cGMP is an important messenger molecule for converting light into electrical signals in the retina, too much of it is toxic. Graybug is advancing a drug targeting cGMP toward concept testing in humans. Their work also includes development of a drug delivery system. This group previously discovered that inhibition of this enzyme can bring the rapid degeneration of light-sensitive cells to a halt, thereby preserving retinal structure and function.
“Testing the efficacy of a deuterated form of DHA as a mutation independent therapy in retinitis pigmentosa”
The Diana Davis Spencer Translational Research Acceleration Award
This joint effort from BioJiva and the lab of Maureen McCall, PhD, University of Louisville, is determining if a novel mutation-independent oral drug candidate can preserve retinal cones and cone function despite rod death in retinitis pigmentosa. To accomplish this goal, they are evaluating a deuterated DHA analogue (D-DHA) in two complementary animal models of chronic RP (a juvenile pig model with early RP onset and an adult mouse model with late RP onset). Both harbor a common rhodopsin mutation, Pro23His. The animals will receive the D-DHA through their diet.
“Simulation of fatty acid oxidation to diminish drusen in AMD”
James Hurley, PhD
University of Washington
The hallmark of dry age-related macular degeneration is the accumulation of potentially harmful deposits under the retina known as drusen, which contain materials made from fatty acids. Dr. Hurley is evaluating a pharmacological strategy that enhances oxidation of fatty acids in retinal pigment epithelial cells to minimize drusen buildup and vision loss.
“Characterization and mitigation of ocular inflammation from AAV gene therapies”
William Beltran, DVM, PhD
University of Pennsylvania School of Veterinary Medicine
Dr. Beltran and his team are improving the safety of gene therapies that use viral vectors to deliver the therapeutic gene to retinal cells. As more inherited retinal disease gene therapies move from the preclinical stage in animal models to clinical trials, there is an increasing recognition of the need to better understand gene therapy-associated inflammation. This inflammatory response can impede the therapy’s performance and cause retinal damage.
“Reconstruction of the RPE-photoreceptor interface via sequential transplantation of iPSC-derived RPE and photoreceptors”
Marius Ader, PhD
Technische Universität Dresden
Dr. Ader is developing a cell transplantation technology for the replacement of retinal pigment epithelial (RPE) and photoreceptor cells in retinal degenerative diseases. The approach is designed to work independently of the underlying cause. In some retinal diseases, including various forms of macular degeneration, both RPE cells and photoreceptors degenerate. The expected results of this study will provide essential insights into the potential use of RPE and photoreceptors produced from induced pluripotent stem cell lines that are less likely to lead to an immune reaction when transplanted.
Individual Investigator Research Awards
“Endogenous repair and regeneration in a human 3D retinal organoid model of Leber congenital amaurosis”
Karl Wahlin, PhD
University of California, San Diego
Dr. Wahlin and his team are developing 3D retinal organoid models to better understand which transcription factors lead to the formation of rod and cone photoreceptors. Using the knowledge gleaned from their initial study, they will explore how to activate and leverage these transcription factors to enable Muller glial cells in the retina to sprout new photoreceptors for vision restoration.
“Exon skipping as an approach to treating EYS-associated retinitis pigmentosa”
Kinga Bujakowska, PhD
Massachusetts Eye and Ear, Harvard Medical School
Mutations in the EYS gene are a leading cause of retinitis pigmentosa (RP). However, the gene is relatively large, exceeding the capacity of current gene therapy delivery systems. As an alternative to gene therapy, Dr. Bujakowska will evaluate exon skipping as a therapeutic approach in zebrafish and human retinal organoid models of EYS-associated RP. Exon skipping involves the use of technologies such as CRISPR/Cas9 or antisense oligonucleotides to skip over mutated regions of the gene so that production of functional protein can be restored.
“Activation of cellular proteostasis as an approach to treat inherited retinal degenerations”
Vadim Arshavsky, PhD
Dr. Arshavsky is evaluating the therapeutic efficacy of proteasome-activating pharmacological compounds for the treatment of inherited retinal degenerations in mouse models. The proteasome is responsible for the degradation of mutant and damaged proteins; therefore, increasing its activity has the potential to reduce the amount of toxic protein build up seen in some retinal diseases. Dr. Arshavsky and his team previously showed that photoreceptors affected by a broad spectrum of disease-causing mutations suffer from a condition called “proteasomal overload,” defined as an insufficient capacity of the cellular protein degradation machinery to process abnormal amounts of misfolded or damaged mutant proteins.
“Identifying mechanisms of Stargardt disease from zebrafish models”
Abigail Jensen, PhD
University of Massachusetts, Amherst
Dr. Jensen is identifying the cellular and molecular processes that contribute to cone photoreceptor loss in Stargardt disease. Her group has developed molecular tools, and imaging capabilities to precisely define and characterize the process of cone dysfunction in zebrafish retinal degeneration models. Unlike rodents, zebrafish have cone-rich retinas and therefore may make more ideal models, more similar to human retinal disease, for evaluating disease processes and potential therapies.
“Cone-dominant tree shrews to model human cone dystrophies”
Deepak Lamba, PhD
University of California, San Francisco
Dr. Lamba is developing a novel stem-cell based organoid model to study cone-based disorders using induced pluripotent stem cells derived from tree shrews, small mammals with cone-rich retinas. Upon completion of the project, he and his team will have developed a novel retinal model that closely mimics the human fovea and a system to understand central retinal degeneration affecting cone photoreceptors. The model will be useful for testing potential therapies.
“Establishment and characterization of a pig model for Usher syndrome type 1B”
Uwe Wolfrum, PhD
Johannes Gutenberg University Mainz
Save Sight Now
Dr. Wolfrum is using pigs born with Usher syndrome type 1B (mutations in MYO7A) to characterize disease mechanisms and test potential therapies in the retina and inner ear. Current Usher syndrome rodent models are not ideal because they don’t exhibit vision loss due to structural differences between rodent and human retinas. Furthermore, the pig eye is closer in size to the human eye, which makes it a better platform for testing potential retinal therapies.
“Systematic and scalable analysis of genomic data to identify novel inherited retinal degenerative disease genes and mutations”
Rinki Ratnapriya, PhD
Baylor College of Medicine
Though researchers have identified disease-causing mutations in more than 270 genes, about one-third of inherited retinal disease (IRD) patients don’t have their mutated gene identified after genetic testing. Genes such as NRL, CRX, and OTX2 are known to regulate many other genes in the retina. Dr. Ratnapriya hypothesizes that genes regulated by NRL, CRX, and OTX2 may be good candidates for causing IRDs, if mutated. When candidate genes are identified, she will look for the mutated candidates in people whose mutated gene wasn’t previously found.
Research Core Awards
“Modeling Usher syndrome type 1B and 2A using human retinal organoids”Mark Pennesi, MD, PhD
Oregon Health & Science University
Save Sight Now
Dr. Pennesi and his team are developing human retinal organoid models of USH1B- and USH2A-mediated retinal degeneration derived from patients’ induced pluripotent stem cells to gain a better understanding of disease mechanisms and progression. The models will also be helpful in testing therapeutic interventions.
“Exploring development of pig model for CRB1 disease”
Maureen McCall, PhD
University of Louisville
Dr. McCall and her team are exploring development of a pig model for inherited retinal diseases caused by CRB1 mutations to better understand how the changes in protein structure and expression lead to vision loss. The model, if developed, would be helpful for testing emerging CRB1 therapies.
Program Project Awards
“Fighting Usher syndrome type 1B: disease pathogenesis and treatment solutions”
Isabelle Audo, MD, PhD
Fondation Voir et Entendre;
Aziz El-Amraoui, PhD
Deniz Dalkara, PhD
Fondation Voir et Entendre
Save Sight Now
Dr. Audo and her team are advancing knowledge about Usher syndrome type 1B from clinical findings, disease mechanisms, and current approaches on gene/protein delivery and therapeutic strategies to prevent or alleviate vision deterioration in USH1B. With access to a large USH1B patient population, they are defining onset, progression, and severity of photoreceptors cell death, contributions of rods and cones involved, and biomarkers for severity and progression. The team will also evaluate CRISPR/Cas9 gene editing as an approach to correcting mutations in the MYO7A gene.
“Investigating the novel disease mechanism for autosomal dominant RP17 and exploring therapeutic approaches”
Alison Hardcastle, PhD
UCL Institute of Ophthalmology;
Susanne Roosing, PhD
Radboud UMC, The Netherlands;
Michael Cheetham, PhD
UCL Institute of Ophthalmology, London, UK
RP17 is a form of autosomal dominant retinitis pigmentosa (adRP) that has remained genetically unsolved for more than 35 years. Dr. Hardcastle and her colleagues identified unusual structural variants on chromosome 17 that caused RP17. The project is looking for these variants in unsolved RP cases worldwide so that they can help with a clinical diagnosis and identify individuals who could be recruited to a clinical trial as therapies are being developed. The project will also examine RP17-affected retinas in a dish to understand the impacts of the structural variants. An RP17 mouse model will also be developed for testing a potential therapy.
Free Family Foundation AMD Award
“Preclinical Testing of Complement Factor H Gene Augmentation Therapy to Treat Dry AMD”
Catherine Bowes Rickman, PhD
John Flannery, PhD
University of California, Berkley
Free Family Foundation
Dr. Bowes Rickman and Dr. Flannery are developing and testing a complement-based gene therapy for dry AMD to restore complement regulation to the site of disease initiation, the retinal pigment epithelium (RPE)-choroid interface, using adeno-associated (AAV) vectors, similar to those in current clinical testing for gene delivery for retinal dystrophies. Complement dysregulation is a well-known factor contributing to the onset of AMD. The approach uses newly developed AAV vectors that transduce the RPE following intravitreal injection in contrast to subretinal injections.
Career Development Awards
“Metabolic uncoupling and AMD: assessing the bioenergetic crisis of the outer retina”
Thomas Wubben, MD, PhD
University of Michigan
Photoreceptors (PRs) and the retinal pigment epithelium (RPE) are two cell types which degenerate in dry AMD and lead to central vision loss. These cells are metabolically coupled to promote and enhance their respective survival and function. In dry AMD, this delicate metabolic balance becomes disrupted. Dr. Wubben is evaluating a recent preclinical model that recapitulates PR metabolic adaptations observed in AMD to better understand the imbalance and identify potential therapeutic targets.
“Investigation of the role of TUBGCP4 and TUBGCP6 in the development of the retinal vasculature”
Lesley Everett, MD, PhD
Oregon Health & Science University
The Diana Davis Spencer Career Development Award
Mutations in the genes TUBGCP4 and TUBGCP6 were recently identified in pediatric patients with an autosomal recessive disease characterized by microcephaly and abnormal retinal vascular development (in some cases, complete absence of retinal vessels). These patients also exhibit diffuse chorioretinal atrophy, resulting in profound vision loss. Dr. Everett is determining the role of TUBGCP4 and TUBGCP6 in chorioretinopathy and retinal vascular development and whether these mutated genes represent novel therapeutic targets to inhibit abnormal blood vessel growth. She will be evaluating the genes’ roles in mouse and cellular models.
“Determination of Genetic Causality in Elusive Unsolved IRD Cases”
Priya Gupta, MD
Clinical Research Fellowship Award (CRFA)
The goal of Dr. Gupta’s research project is to find answers for currently difficult to solve retinal disease genetic identification cases using more advanced methods of gene sequencing, specifically whole genome sequencing. Whole genome sequencing has the added benefit of identifying disease-causing variants, not just in coding regions of a gene, but also in noncoding areas of the genome that are often important for gene expression, regulation, and splicing.
“Characterization and optimization of dark-adapted two-color fundus perimetry in patients with inherited retinal disease”
Alessia Amato, MD
Università Vita-Salute San Raffaele
Clinical Research Fellowship Award (CRFA)
Two-color dark adapted perimetry (2cDAP) is an emerging clinical diagnostic tool for the characterization of the pattern of rod versus cone-dependent deficits across a patient’s visual field. This clinical tool is becoming ever more important in gene therapy clinical trials (especially for retinitis pigmentosa), given its ability to localize and quantify changes in rod-driven photoreceptor responses in dark adapted (scotopic) conditions in patients with inherited retinal disease. Preliminary studies of 2cDAP have demonstrated significant clinical utility for this diagnostic modality, but much work remains to be done in order to further optimize and characterize these studies in a broader set of inherited retinal disease patients for future clinical applications.
“PRPF31-associated retinitis pigmentosa: Clinical and genetic characterization in humans and gene augmentation therapy in a non-human primate model”
University of Pittsburgh, University of Pittsburgh Medical Center
Clinical Research Fellowship Award (CRFA)
Dr. Aweidah’s research program includes the development of a RP-PRPF31 database characterizing clinical and genetic features of this disease and will establish a platform for evaluating efficient gene therapies for PRPF31-RP in clinical trials. In addition, he will develop a non-human primate (NHP) manifesting the PRPF31-associated retinitis pigmentosa using CRISPR/Cas9-mediated knock-down. This NHP model of PRPF31 will then be used to test AAV-mediated PRPF31 augmentation therapy.