University of Wisconsin-Madison Awarded $29 Million NIH Common Fund Grant to Develop LCA16 and Best Disease Gene-Editing Therapies

The five-year grant will advance the emerging treatments toward clinical trials

A multi-disciplinary retinal research team from the University of Wisconsin-Madison (UWM) has been awarded a five-year, $29 million U19 grant from the National Institutes of Health (NIH) Common Fund to develop CRISPR/Cas9 gene-editing treatments for two inherited retinal conditions: Best disease caused by the R218C mutation in the BEST1 gene and Leber congenital amaurosis 16 (LCA16) caused by the W53X mutation in the KCNJ13 gene. Known as The CRISPR Vision Program: Nonviral Genome Editing Platforms to Treat Inherited Retinal Channelopathies, the grant will advance the LCA16 and Best disease treatments toward evaluation in clinical trials.

“We are delighted to receive significant support through the Common Fund grant to drive the development of innovative gene-editing treatments for these blinding retinal diseases,” says Bikash Pattnaik, PhD, associate professor of pediatrics, ophthalmology and visual sciences at UWM, and one of the project’s lead investigators. “We also appreciate earlier support from the Foundation Fighting Blindness for Best disease and LCA16 research that positioned us well to receive the award.”

The other lead UWM investigators for the project include Krishanu Saha, PhD, associate professor of biomedical engineering and faculty member of the Wisconsin Institute for Discovery (WID); David Gamm, MD, PhD, professor of ophthalmology and visual sciences and director of the McPherson Eye Research Institution; and Shaoqin “Sarah” Gong, PhD, professor of ophthalmology and visual sciences and biomedical engineering and WID faculty. Investigators at Spotlight Therapeutics, the Morgridge Institute for Research, and the UMass Chan Medical School will work closely with the UWM team on the project.

The NIH Common Fund is a unique resource for support of high-risk, innovative endeavors with the potential for extraordinary impact. Common Fund programs are short-term, goal-driven strategic investments, with deliverables intended to catalyze research across multiple biomedical research disciplines. The LCA16 and Best disease research award is administered by the National Institute of Neurological Disorders and Stroke (NINDS) on behalf of the NIH. 

The Foundation has accepted an invitation to be a member of the External Advisory Board for the award. Chad Jackson, PhD, the Foundation's senior director of preclinical translational Research, will advise on project design, analysis, interpretation, and regulatory strategy.

Best disease is a form of inherited macular degeneration that can lead to significant central vision loss. LCA16 causes significant central and peripheral vision loss in young children. The gene mutations for both conditions affect the function and health of retinal pigment epithelial (RPE) cells which provide critical support for photoreceptors, the retinal cells that process light to make vision possible. Loss and dysfunction of RPE cells lead to loss of photoreceptors.

CRISPR/Cas9 gene editing is an emerging therapeutic approach that works like a pair of molecular scissors to cut out or modify the mutated region of the gene. Gene editing is different from gene (replacement) therapy. In gene therapy, copies of an entirely new gene are delivered to the retina to replace the defective copies. In CRISPR/Cas9 gene editing, only the mutated region of the gene is corrected.

For both the LCA16 and Best disease projects, the investigators will use induced pluripotent stem cells (iPSCs) to create human models of the conditions to evaluate the CRISPR/Cas9 treatments. The team will extract a small sample of skin or blood cells from patients and tweak the cells so they revert to a stem-cell-like state. Then, the cells will be coaxed forward to differentiate into RPE cells. The team will also evaluate the LCA16 CRISPR/Cas9 treatment in a mouse model.

The investigators will evaluate two non-viral delivery approaches for emerging treatments. One approach will use nanoparticles — tiny manmade particles with a diameter smaller than that of human hair — to deliver the CRISPR/Cas9 treatment into the RPE cells. The other delivery approach will use ribonucleoproteins (RNPs) for treatment delivery. RNPs can be modified with a cell-targeting antibody and a cell-penetrating peptide to facilitate delivery of the CRISPR/Cas9 treatment into cells and enable efficient editing of the targeted DNA. Both the nanoparticle and the RNP delivery systems can potentially lower the risk of inflammation and off-target editing. These attributes may provide opportunities for safe redosing of the therapy, potentially overcoming a key limitation of traditional viral gene therapies.