2026 BDGRI Grant Recipients
Determining the gene correction threshold required to cure CLN2 disease.
| CHIEF INVESTIGATOR: | Professor Alex Hewitt |
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| AFFILIATION: | Menzies Institute for Medical Research, University of Tasmania, Australia |
| AMOUNT: | USD $50,000 |
Hewitt
Professor Alex Hewitt obtained his PhD investigating the molecular and phenotypic associations for open-angle glaucoma in 2009 and completed formal Ophthalmology training at the Royal Victorian Eye and Ear Hospital in Melbourne in 2011. To date, Alex is a co-author on over 400 peer-reviewed publications, which have been cited more than 30,000 times. His team has been applying CRISPR/Cas-gene editing technology to better understand and treat inherited diseases.
Project Summary:
Existing treatments for CLN2-related disease aim to slow disease progression but do not permanently fix the underlying genetic problem.
One promising approach is gene therapy, where a functional copy of the gene is delivered to brain cells using a virus known as an adeno-associated virus. While this strategy can help, it has important limitations. The added gene may stop working over time, and the immune system can prevent the treatment from being given more than once. As a result, we are exploring gene editing, which aims to permanently correct the faulty gene itself.
Gene editing tools can precisely change specific variants in the DNA sequence, but these gene editing tools are large and difficult to deliver to brain cells. To fit them into an adeno-associated virus, the editors must be split into two pieces and reassembled inside the cell. Current methods rely on the two pieces joining together at the protein level, which is inefficient and often results in too little repair to make a meaningful difference.
In our early studies, we showed that a disease-causing mutation in the TPP1 gene can be corrected in the laboratory using a gene-editing tool called a base editor. However, when we tested this approach in mice with Batten disease, the treatment did not improve survival. We believe this is because the gene editor did not reassemble efficiently enough inside brain cells.
To solve this problem, we propose to use a new technology called “stitchR”, which allows the two halves of a gene editor to be joined together earlier at the messenger RNA stage before the protein is made. This approach has been shown to be much more efficient and could allow enough gene editing to restore normal TPP1 function in brain cells.
This project will test whether delivering stitchR-enabled gene editors using two separate adeno-associated viruses can successfully repair the faulty TPP1 gene in the brain. We will also explore an alternative gene-repair strategy using integrase enzymes, which may offer additional advantages.
By directly comparing different gene-based treatments, this research aims to identify the most effective and durable strategy for treating CLN2-related Batten disease. Ultimately, this research will help accelerate the development of once-off curative therapy.
The BDGRI gratefully acknowledges our Funding Partner, Jack’s Thousand Days Foundation, for their generous support of this project.
Preclinical studies comparing potential therapeutics in a patient-derived human retina cell model of CLN3-Batten disease.
| CHIEF INVESTIGATOR: | A/Prof Ruchira Singh |
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| AFFILIATION: | University of Rochester, New York, USA |
| AMOUNT: |
USD $50,000
|
Singh
Ruchira Singh, PhD, is an Associate Professor in the Departments of Ophthalmology and Biomedical Genetics at the University of Rochester Medical Center. Her research focuses on developing treatments for retinal and neurodegenerative diseases using patient-derived human induced pluripotent stem cells (hiPSCs) and advanced retinal disease models. Dr Singh’s work aims to better understand the cellular mechanisms underlying retinal degeneration and to identify potential therapeutic strategies for disorders, including Batten disease. Her laboratory has contributed important insights into CLN3 retinal pathology and the development of human retinal models for translational research.
Project Summary:
Progressive vision loss, which ultimately leads to blindness, is seen in all patients with CLN3-Batten disease (CLN3 disease). Currently, there are no effective treatments for any CLN3 disease symptoms. A major hurdle for developing practical and safe treatments is the absence of a human CLN3 disease model for therapeutic testing, as treatments developed and tested in animal models of other human diseases have routinely failed to work in human patients. To be able to effectively test potential treatment options in patients’ own cells, our laboratory recently developed a patient-derived eye (retina) cell model of CLN3 disease. This patient-derived eye cell model of CLN3 disease shows important disease-associated features of the human CLN3 disease, including loss of light-sensing photoreceptor cells and retina degeneration. Using this patient-derived eye cell model, we have recently identified recombinant human acid ceramidase as a promising treatment for targeting vision loss in CLN3 disease. In this research project, we will use this patient-derived eye cell model to compare the safety and effectiveness of rhAC to other promising treatment strategies (like Miglustat) that have shown initial success in cell culture models, animal models, and clinical studies. We will also evaluate the effectiveness of individual treatment strategies (example: Miglustat) when the treatment is initiated 1) before the CLN3 disease patient-derived eye cell model shows any disease symptoms, 2) when the patient-derived eye cell model shows symptoms of early-stage disease, and iii) when the patient-derived eye cell model shows symptoms of late-stage disease. Overall, our patient-derived eye cell model of CLN3 disease allows us to evaluate and compare the effectiveness of promising treatment strategies at different stages of the disease, and even before the cells start showing disease symptoms.
We expect that the completion of this project will i) provide viable and safe treatment options that will be ready to be tested in human patients with CLN3 disease and ii) inform on the optimal and feasible disease stage for therapeutic intervention with specific treatment strategies like Miglustat.
This project was selected for funding through the 2026 BDGRI round by our collaborators, the Batten Disease Clinical Research Consortium (BDCRC).
The BDGRI is proud to collaborate with the BDCRC, which is supported through the National Institutes of Health (NIH) Rare Diseases Clinical Research Network framework in the United States — recognizing Batten disease as a priority area for collaborative rare disease research and therapeutic development.
An Antisense Therapy for DNAJC5 knockdown in CLN4 Batten Disease.
| CHIEF INVESTIGATORS: | Timothy Yu, MD, PhD, and Milen Velinov, MD, PhD |
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| AFFILIATION: | Boston Children’s Hospital, Massachusetts, USA (Yu), and Rutgers Robert Wood Johnson Medical School, New Jersey, USA (Velinov) |
| AMOUNT: |
USD $50,000
|
Yu
Dr. Yu is a physician-scientist in the Division of Genetics & Genomics at Boston Children’s Hospital and Harvard Medical School whose research group that works at the intersection of genomics, informatics, and neurobiology to better understand, diagnose, and treat neurogenetic disease. His group has pioneered new models for interventional genomic medicine, beginning with the 2018 development of a patient-customized antisense oligonucleotide for a young girl with CLN7 Batten disease. This and subsequent work by his group and others have served as the basis for new FDA guidances for individualized medicines released in 2021 and 2026, and he continues to work closely with patients, foundations, physicians, and regulators to fortify these pathways. He is founder of the N=1 Collaborative, and a recipient of the NORD Rare Impact Award, the American Neurologic Association’s Denny-Brown Young Neurologic Scholar Award, the Society for Pediatric Research Award in Honor of E. Mead Johnson, and the American Society of Gene and Cell Therapy’s Jerry Mendell Award for Translational Science.
Velinov
Dr. Milen Velinov, MD, PhD, is a Professor of Pediatrics and Genetics at Rutgers University, and The Director of the Division of Genetics at the Department of Pediatrics, Rutgers Robert Wood Johnson Medical School. He is a practicing physician and an active researcher, largely focused on studying the molecular basis and the natural history of genetic disorders, including Batten Disease. Dr. Velinov was the PI of the Staten Island-based Batten Registry at the Institute for Basic Research in Developmental Disabilities for over 10 years. His research has helped identify the molecular basis of DNAJC5-associated Adult-Onset Neuronal Ceroid Lipofuscinosis (CLN4 type Batten Disease). He collaborated with researchers from Cornell University, Yale University, and Calgary University to show that DNAJC5-associated NCL develops following a dominant-negative pathway and may be ameliorated by selectively downregulating the mutant DNAJC5 allele. In addition to DNAJC5-associated NCL, Dr. Velinov’s research interests include Fragile X syndrome, DOCK3, and DEAF1-associated disorders.
Project Summary:
CLN4 is a rare Batten disease that affects young adults, causing seizures, memory loss, and neurological decline. This condition stems from harmful changes in the DNAJC5 gene, which produces CSPα, a protein vital for healthy brain functions. In CLN4, genetic mutations cause CSPα to malfunction, leading to irreversible brain cell damage and death. Presently, no approved treatment exists.
Our project seeks to develop antisense oligonucleotides, small pieces of DNA, to decrease harmful CSPα production. We will deliver ASOs to lab-grown cells from CLN4 patients and test their ability to reduce disease-causing effects. Success could offer new treatment pathways for CLN4.
The BDGRI gratefully acknowledges our Funding Partner, the Allandale Foundation, for their generous support of this project.