Foundation Funds 25 New Grants Totaling $15.1 Million in FY23

The Foundation Fighting Blindness added 25 new research projects to its portfolio, an investment totaling $15.1 million, during its Fiscal Year 2023 (ending June 30, 2023). Project awards ranged from early-stage lab research to identify treatment targets to translational efforts for advancing emerging therapies toward clinical trials.

Examples of FY2023 grants include:

• Developing treatments that use prime editing — a state-of-the-art gene-editing technology — to more safely and effectively correct a broader range of mutations in retinal disease genes.
• Identifying new genetic causes and risk factors for age-related macular degeneration and inherited retinal diseases.
• Advancing several gene-agnostic therapies as well as treatments that target specific genes including: MYO7A (USH1B), ABCA4 (Stargardt disease), PRPH2 (RP and macular conditions), MERTK (RP), and CRX (Leber congenital amaurosis).

“Excitingly, 15 of the new awardees for FY23 are researchers never previously funded by the Foundation,” said Claire Gelfman, PhD, chief scientific officer at the Foundation. “We make the greatest impact in driving our urgent mission to eradicate all retinal degenerative diseases when we continually infuse our efforts with new ideas and research talent.”

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 93 grants. The research projects are conducted by more than 96 research investigators at 71 institutions around the world. In addition to funding researchers in the United States, the Foundation funding extends internationally to laboratories in Australia, Belgium, Brazil, Canada, Denmark, England, Finland, France, Germany, Israel, Italy, Mexico, the Netherlands, Poland, Spain, and Switzerland.

Translational Research Acceleration Program Awards

Krzysztof Palczewski, PhD, MS
$900,000
The Regents of the University of California, Irvine

“Correcting previously untreatable retinal degenerative diseases using twin prime editing.”

Dr. Palczewski is developing a novel gene-editing technology called twin prime editing for treating a model of Stargardt disease. He is also developing a twin prime editing framework to address other inherited retinal degenerative diseases. Prime editing enables changes (corrections) to DNA to be made through single-strand breaks which are safer and more reliable than double-strand breaks used in earlier gene-editing technologies. Twin prime editing introduces additional flexibility by enabling the deletion and/or insertion of large DNA sequences for addressing a broader range of mutations.

François Paquet-Durand, PhD
$989,000
Mireca Medicines GmbH

“Clinical translation of a mutation-independent treatment for hereditary retinal degeneration using BlockPKG, an inhibitory cGMP analogue.”

Mireca Medicines is developing a drug and delivery system targeting excessive cGMP-signaling that leads to loss of photoreceptors. This signaling molecule can over-activate the enzyme protein kinase G (PKG). This group previously discovered that inhibition of this enzyme can bring the rapid degeneration of light-sensitive cells to a halt and thereby preserving retinal structure and function. The group is working to advance the emerging treatment toward a clinical trial.

Kathryn Pepple, MD, PhD
$900,000
University of Washington

“Evaluating mitigation strategies for intravitreal viral vector-mediated inflammation across animal models.”

Dr. Pepple is investigating novel strategies for mitigating ocular inflammation which can result from intravitreal injection of viral gene therapies. She is evaluating animal model data and performing detailed immunologic characterization of the non-human primate eyes during ocular inflammation to provide clinical-pathologic correlations and biomarker validation for use in human clinical studies. A robust and evidence-based approach to preventing ocular inflammation following intravitreal adeno-associated virus (AAV)-mediated gene therapy is a critical unmet need.

Baerbel Rohrer, PhD
$900,000
MitoChem Therapeutics

“Targeting the molecule FUS for neuroprotection: A novel therapeutic approach in retinal degeneration.”

Dr. Rohrer and her team are determining if a small molecule (MC16) can extend the lifespan of retinal cells by targeting mitochondria, which produce cellular energy.  The molecule has the potential to significantly decrease the age-dependent and/or stress-dependent movement of a protein associated with mitochondrial dysfunction observed in retinal degeneration.

Renee Ryals, PhD
$887,955
Casey Eye Institute, Oregon Health & Science University

“Lipid nanoparticle-mediated gene editing for IRD patients harboring PRPH2 mutations.”

Dr. Ryals is investigating prime editing delivered by lipid nanoparticles for correcting mutations in the PRPH2 gene, which is correlated with certain retinal diseases. Dr. Ryals is deriving induced pluripotent stem cells (iPSCs) from patient blood and differentiating them into human retinal organoids for therapeutic testing.  Retinal organoids are three-dimensional structures, which have some similarities to the human retina (including the photoreceptors), thereby serving as effective models of retinal development and testing platforms.

Free Family AMD Research Award

Stephen Tsang, MD, PhD, and Marta Olah, PhD
$600,000
Columbia University

“ARMS2/HTRA1 in non–cell-autonomous oxidative and anti-inflammatory therapeutic targeting.”

Drs. Tsang and Olah are using CRISPR/Cas9 gene-editing to identify genetic variations and mutations that lead to age-related macular degeneration (AMD). They are also investigating stress signals from microglia (resident immune cells of the brain and retina) in AMD that might be a therapeutic target to reduce AMD-related cell death. They will also explore whether the presence of at least one low-risk ARMS2/HTRA1 allele (gene copy) maintains oxidative, anti-inflammatory, and overall cellular health in microglia.

Program Project Awards

Silvia Finnemann, PhD
$2,472,518
Fordham University

“A novel, rationally designed pharmacological approach to countering vision loss in a preclinical model of MERTK-associated retinitis pigmentosa.”

Dr. Finnemann and her team are determining if an early-onset inflammatory response in retinal pigment epithelial (RPE) cells precedes photoreceptor degeneration. RPE cells provide provide critical support for photoreceptors. If successful in uncovering this novel disease pathway, a therapeutic strategy testing anti-inflammatory drugs for MERTK-associated retinitis pigmentosa will be proposed to prevent or significantly delay retinal degeneration.

Dror Sharon, PhD
$2,500,000
Hadassah-Hebrew University Medical Center

“In vivo retinal RNA editing using the cellular adenosine deaminase acting on RNA (ADAR) enzyme.”

Dr. Sharon and his team are developing an RNA editing technology to correct specific retinal disease-causing mutations. They are delivering novel biological machinery to the retina that uses enzymes called “adenosine deaminase acting on RNA” or ADAR that serves as molecular editors to correct a specific mutation in RNA. The technique is like gene editing but instead of editing the gene, this technique edits RNA, which is the transcript or message read from the gene to produce protein.

Individual Investigator Research Awards

Esther Biswas-Fiss, MS, PhD
$300,000
University of Delaware

“Deciphering the impact of ABCA4 genetic variants of unknown significance in inherited retinal disease prognosis.”

Dr. Biswas-Fiss is using computational modeling and experiments to determine whether ABCA4 variants of unknown significance (VUSs) lead to ABCA4-related disease. Resolving these VUSs is critical for patients to meet inclusion criteria in clinical trials for ABCA4 therapies. Mutations in ABCA4 cause the vast majority of Stargardt disease cases.

Yu Holly Chen, PhD
$300,000
University of Alabama at Birmingham

“Restoring extracellular matrix signaling between Müller glia and photoreceptors for therapies of inherited retinal degeneration.”

Dr. Chen is seeking to better understand the role of muller glia (MG) in the early stages of inherited retinal diseases. MG provide functional and structural support to photoreceptors and other cells in the retina. Using human-derived mini-retinas, she is determining the cause of MG dysfunction, assessing the negative impact of MG cell dysfunction on photoreceptor development, and exploring the feasibility of rescuing photoreceptors by restoring extracellular matrix signaling, which typically helps cells attach and communicate with nearby cells.

Frauke Coppieters, MSc, PhD
$300,000
Ghent University

“Long non-coding RNAs (lncRNAs) as molecular drivers and therapeutics targets of inherited retinal disease.”

Dr. Coppieters is using in-house and public data sets to identify inherited retinal disease (IRD)-related long non-coding RNA (lncRNA) in the retina and retinal pigment epithelium to create a comprehensive catalog of lncRNA with a potential role in IRDs. Long non-coding RNA does not convert code into protein but are part of regulating gene expression at the right time and place. This project will evaluate the therapeutic potential of selected lncRNAs in IRD patient models.

Manuel Irimia, PhD
$300,000
Centre for Genomic Regulation (CRG)

“Identification, validation and modulation of uncharacterized splicing mutations in inherited retinal diseases.”

Dr. Irimia is seeking to uncover novel genetic variants that cause splicing misregulation, leading to inherited retinal diseases (IRDs). This project aims to identify new variants in IRD genes that change the way the different pieces of a gene are combined together to make a functional protein. Potential variants identified through genetic sequencing will be tested in the lab to see if their presence has a detrimental effect on gene production and retinal cell biology.

Simon Petersen-Jones, DVetMed, PhD, DVOphthal, DECVO
$300,000
Michigan State University

“Knock-down and replacement therapy for dominant CRX-associated retinopathies.”

Dr. Petersen-Jones is testing a gene knock-down strategy for dominant CRX-associated inherited retinal diseases (including CRX-associated autosomal dominant Leber congenital amaurosis). A single, mutated copy of CRX can cause disease. This strategy will stop the bad copy of CRX and add back a good copy of CRX using artificial microRNA. MicroRNA are small non-coding RNA involved in RNA silencing and regulating gene expression. Dr. Petersen-Jones will test this knockdown and replace technique on CRX as a proof of concept that can be modified for other dominantly inherited diseases.

Peter Quinn, PhD
$300,000
Columbia University

“Prime editing for PRPH2 inherited retinal dystrophies.”

Dr. Quinn is testing a prime editing technique for multiple mutations in PRPH2 using patient-derived retinal organoids. Prime editing is a gene editing technique that splices directly at the site of the mutations and switches out a bad copy of the gene with a good copy. Successful completion of this project will establish a preclinical pathway for proof-of-concept for PRPH2 prime editing therapeutics and lay the foundation for the same strategy to be applied to other IRDs.

Thomas Reh, PhD
$300,000
University of Washington

“Reprogramming human MG to retinal progenitors and neurons.”

Dr. Reh is exploring approaches for enabling retinal cells called Müller glia (MG) to sprout new photoreceptors. Previous experiments have shown this is possible by delivering a transcription factor known as ascl1 to the MG. Dr. Reh is now optimizing photoreceptor regeneration in a 3D culture system that more closely resembles the human retina. He is seeking to improve and optimize the viral delivery of a gene expressing ascl1 for moving the approach closer to evaluation in a clinical trial.

Melanie Samuel, PhD
$300,000
Baylor College of Medicine

“Targeting microglia to prevent retinal neuron loss in inherited retinal degenerations.”

Dr. Samuel is attempting to limit the damage done by microglia (clean-up cells) in the retina by removing signal regulatory protein alpha (SIRPα). Removing SIRPα should slow excessive cleaning activity in the cell-based model and may improve survival of transplanted photoreceptors. This project could potentially lead to a therapeutic approach for slowing vision loss for a broad range of inherited retinal diseases.

Career Development Awards

Robert Hyde, MD, PhD - $375,000
University of Illinois-Chicago

“Inner retinal dysfunction in retinitis pigmentosa.”

Dr. Hyde is using a novel electroretinography (ERG) protocol in animal models of retinal degeneration to determine whether retinal remodeling leads to aberrant responses from inner retinal neurons that mask relevant responses to visual stimuli. ERG is a non-invasive means to measure the electrical responses of various retinal cell types to light. Inner retinal remodeling can cause aberrant inner retinal responses that limit the potential for functional improvement from therapies that improve photoreceptor function.

Debarshi Mustafi, MD, PhD
$375,000
University of Washington

“Deciphering the missing heritability in inherited retinal diseases with targeted long-read genome sequencing.”

Dr. Mustafi is using long-read DNA sequencing technology to identify heritability in cases where standard genetic testing does not provide an answer due to hidden non-coding variants. Long-read sequencing is used to identify large structural variants including large DNA deletions and insertions. Autosomal recessive inheritance requires two mutated variants, and in many cases, only one or no variants are located in patients with clinical features of an inherited retinal disease (IRD). Dr. Mustafi will analyze cases where only one variant for ABCA4 and USH2A patients have been identified through genetic testing and more in-depth mapping of the genome may result in the detection of a second non-coding variant. This data will be used to expand the gene panel testing of IRD patients to look for rare variants currently not included in standard testing.

Katherine Uyhazi, MD, PhD
$375,000
University of Pennsylvania

“Investigating the heterogeneity of photoreceptor precursor cells for retinal regeneration.”

Dr. Uyhazi is seeking to better understand the different stages of photoreceptor precursor cells during development in order to identify the optimal cell type for cell-based therapies, including transplantation. Each novel subpopulation of photoreceptor precursor cells will be tested for their integration into the retina, and if they can increase photoreceptor cell generation.

Clinical Research Fellowship Awards

Anfisa Ayalon, MD
$65,000
University of Pittsburgh

“Spectral properties of ERG oscillatory potentials in hereditary retinal dystrophies prior to and following the application of gene therapy employing a novel gel-based AAV vector delivery system.”

Dr. Ayalon will study the spectral properties of ERG oscillatory potentials (OPs) in hereditary retinal dystrophies and will evaluate if the frequency domain of OPs can be used as a new diagnostic tool. The OPs may be an earlier, and more sensitive, indicator of an inherited retinal disease. Dr. Ayalon will also investigate if the gel-based epiretinal adeno-associated virus (AAV) delivery system has a better retinal cell transduction efficiency than subretinal and intravitreal injections.

Thales Guimaraes, MD
$65,000
Moorfields Eye Hospital NHS Foundation Trust

“Exploring retinal structure and function in patients with CDH23-associated Usher syndrome.”

Dr. Guimaraes will study patients previously confirmed, via genetic testing, with Usher syndrome type 1D due to CDH23 mutations. His aim is to perform several tests, using state-of-the-art cutting-edge technology, to analyze the structure and function of the retina in a group of 25 patients within a period of 12 months. This will be the first study to systematically assess detailed photoreceptor structure and correlate it with measures of visual sensitivity in Usher type 1D.

Clinical Innovation Award

Ramiro Maldonado, MD
$300,000
Duke University

“Ultracompact hand-held swept-source optical coherence tomography as a novel diagnostic modality for early-onset retinal dystrophies.”

Dr. Maldonado is investigating the use of hand-held optical coherence tomography (OCT) to image young pediatric patients, with and without early-onset retinal disease, to establish an ideal protocol for the use of the hand-held system in standard clinical care and clinical trials. The team will also obtain biomarker data related to retinal degeneration, data related to the effect of specific genetic variants, and insights into foveal development using hand-held OCT.

Research Core: Non-Rodent Large Animal Awards

Martha Neuringer, PhD
$499,844
Oregon Health and Science University

“Creation of a translational nonhuman primate model of Usher syndrome 1B.”

Dr. Neuringer and her team will expand a gene-edited nonhuman primate (NHP) model of Usher syndrome for initial tests of gene therapy. The expanded animal models of Usher syndrome 1B (USH1B) will enable studies to determine how closely primates harboring USH1B genetic variation resemble the human disease. The model will also be used to test a new type of gene therapy that uses a dual adeno-associated virus (AAV) platform that can facilitate the delivery of the MYO7A gene, which is too large to fit in a single AAV vector.

Simon Petersen-Jones, DVetMed, PhD, DVOphthal, DECVO
$500,000
Michigan State University

“Characterization of a large animal Stargardt disease model – suitability for translational therapy trials.”

Dr. Petersen-Jones will establish a breeding colony of dogs with Stargardt disease (ABCA4-affected) and determine if the disease progression can be accelerated with vitamin A supplementation. The retina of Stargardt disease patients accumulates material called bisretinoid, a toxic byproduct of vitamin A metabolism, that fluoresces with UV light.  As part of the study, Dr. Petersen-Jones will standardize a way of measuring the amount of autofluorescence in affected dogs.  This has the potential to be a new standard monitoring measurement to grade the rate of disease progression.

FFB Supported Workshop

Cold Spring Harbor Laboratory
$5,000

“2023 Cold Spring Harbor Lab – Vision: A Platform for Linking Circuits, Behavior & Perception.”

Vision: A Platform for Linking Circuits, Behavior & Perception was held in Long Island, New York, between June 16-July 1, 2023. The purpose of the course was to bring together students and faculty for in-depth and high level discussions of modern approaches for probing how specific cell types and circuits give rise to defined categories of visual perception and behavior. It was also designed to address novel strategies aimed at overcoming diseases that compromise visual function.