TRANSLATIONAL RESEARCH ACCELERATION PROGRAM
Rui Chen, PhD – $899,820
Baylor College of Medicine
“Retinal regeneration through an epigenetic therapy”
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.
Graybug Vision – $989,000
“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.
BioJiva – $1,446,827
“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 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.
James Hurley, PhD – $717,724
University of Washington
“Simulation of fatty acid oxidation to diminish drusen in AMD”
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.
William Beltran, DVM, PhD – $1,480,695
University of Pennsylvania School of Veterinary Medicine
“Characterization and mitigation of ocular inflammation from AAV gene therapies”
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.
Marius Ader, PhD – $883,554
Technische Universität Dresden
“Reconstruction of the RPE-photoreceptor interface via sequential transplantation of iPSC-derived RPE and photoreceptors”
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 independent 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 an immune reaction when transplanted.
INDIVIDUAL INVESTIGATOR RESEARCH AWARDS
Karl Wahlin, PhD – $300,000
University of California, San Diego
“Endogenous repair and regeneration in a human 3D retinal organoid model of Leber congenital amaurosis”
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.
Kinga Bujakowska, PhD – $300,000
Massachusetts Eye and Ear, Harvard Medical School
“Exon skipping as an approach to treating EYS-associated retinitis pigmentosa”
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.
Vadim Arshavsky, PhD – $300,000
Duke University
“Activation of cellular proteostasis as an approach to treat inherited retinal degenerations”
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.
Abigail Jensen, PhD – $300,000
University of Massachusetts, Amherst
“Identifying mechanisms of Stargardt disease from zebrafish models”
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.
Deepak Lamba, PhD – $300,000
University of California, San Francisco
“Cone-dominant tree shrews to model human cone dystrophies”
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.
Uwe Wolfrum, PhD – $300,000
Johannes Gutenberg University Mainz
“Establishment and characterization of a pig model for Usher syndrome type 1B”
Funding Partner: 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.
Rinki Ratnapriya, PhD – $300,000
Baylor College of Medicine
“Systematic and scalable analysis of genomic data to identify novel inherited retinal degenerative disease genes and mutations”
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
Mark Pennesi, MD, PhD – $75,000
Oregon Health & Science University
“Modeling Usher syndrome type 1B and 2A using human retinal organoids”
Funding Partner: 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.
Maureen McCall, PhD – $65,830
University of Louisville
“Exploring development of a pig model for CRB1 disease"
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
Isabelle Audo, MD, PhD – Fondation Voir et Entendre
Aziz El-Amraoui, PhD – Institut Pasteur
Deniz Dalkara, PhD – Fondation Voir et Entendre
“Fighting Usher syndrome type 1B: disease pathogenesis and treatment solutions” – $2,317,150
Funding Partner: 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.
Alison Hardcastle, PhD – UCL Institute of Ophthalmology
Susanne Roosing, PhD – Radboud UMC, The Netherlands
Michael Cheetham, PhD – UCL Institute of Ophthalmology, London, UK
“Investigating the novel disease mechanism for autosomal dominant RP17 and exploring therapeutic approaches” –$2,500,000
RP17 is a form of autosomal dominant retinitis pigmentosa (adRP) that had 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 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
Catherine Bowes Rickman, PhD – Duke University
John Flannery, PhD – University of California, Berkley
“Preclinical Testing of Complement Factor H Gene Augmentation Therapy to Treat Dry AMD” – $600,000
Funding Partner: 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
Thomas Wubben, MD, PhD – $375,000
University of Michigan
“Metabolic uncoupling and AMD: assessing the bioenergetic crisis of the outer retina”
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 pre-clinical model that recapitulates PR metabolic adaptations observed in AMD to better understand the imbalance and identify potential therapeutic targets.
Lesley Everett, MD, PhD – $500,000
Oregon Health & Science University
“Investigation of the role of TUBGCP4 and TUBGCP6 in the development of the retinal vasculature”
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.
Priya Gupta, MD – $65,000
Duke University
“Determination of Genetic Causality in Elusive Unsolved IRD Cases”
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.
Alessia Amato, MD – $65,000
Università Vita-Salute San Raffaele
“Characterization and optimization of dark-adapted two-color fundus perimetry in patients with inherited retinal disease”
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.
Hamzah Aweidah – $65,000
University of Pittsburgh, University of Pittsburgh Medical Center
“PRPF31-associated retinitis pigmentosa: Clinical and genetic characterization in humans and gene augmentation therapy in a non-human primate model”
Clinical Research Fellowship Award (CRFA)
Dr. Aweidah’s research program includes 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.
