Systemic delivery of SingleCut CRISPR gene editing components restored dystrophin expression to up to 92 percent of normal expression in heart muscle in canines
First study of Exonics’ SingleCut technology in large mammals supports advancement toward the clinic
Study published online in the journal Science
CAMBRIDGE, Mass. – August 30, 2018 – Exonics Therapeutics, Inc., a biotechnology company focused on developing gene editing therapies to treat patients with Duchenne muscular dystrophy and other neuromuscular diseases, today announced the publication of a preclinical study demonstrating the company’s SingleCut CRISPR technology restored in vivo dystrophin expression in a canine model of Duchenne muscular dystrophy. The research article, titled, “Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy,” was published online in the journal Science.
The preclinical study evaluated both intramuscular and systemic delivery of CRISPR gene editing components in canines with a naturally-occurring splice mutation that leads to deletion of exon 50 of the dystrophin gene. In humans, deletion of exon 50 of the dystrophin gene is one of the most common single exon deletions that causes Duchenne. The study demonstrated that a single systemically delivered dose of adeno-associated viruses (AAVs) encoding the gene-editing enzyme CRISPR/Cas9 and a guide strand RNA efficiently restored the expression of dystrophin, the key protein missing in children with Duchenne. Canines receiving treatment demonstrated expression of dystrophin up to 90 percent of normal levels in skeletal muscle, depending on muscle type, eight weeks after treatment, compared to untreated animals. In the dog receiving the highest dose, cardiac muscle dystrophin expression was restored to 92 percent of normal levels. Notably, no off-target effects of gene editing were detected in the study.
The study was conducted in collaboration with UT Southwestern Medical Center and the Royal Veterinary College (RVC) in London in accordance with full national and local ethical approval. Initial support for the study was provided by CureDuchenne Ventures, the arm of CureDuchenne that funds emerging projects to find treatments for Duchenne.
“The encouraging findings from this preliminary study using Exonics’ SingleCut CRISPR approach are very significant as a model for future translational studies,” said Eric Olson, Ph.D., a co-author of the paper, founder and chief science advisor of Exonics, and professor and chair of the Department of Molecular Biology at UT Southwestern Medical Center. “Canines have clinical and pathological features similar to the human presentation of Duchenne, including muscle weakness, atrophy and fibrosis. These findings build upon our experience in correcting Duchenne mutations in cells from patients and mouse models of the disease. Longer-term studies will enable us to further assess safety and durability of the benefits as we advance our treatment toward clinical studies.”
“Demonstrating the efficacy and safety of Exonics’ SingleCut CRISPR approach in large mammals is an important milestone before evaluating the potential of this approach to treat patients with Duchenne, a devastating muscle disease in children for which new treatment approaches are desperately needed,” said John Ripple, chief executive officer of Exonics. “We look forward to continuing our research to inform the development of a safe and efficacious one-time treatment to repair mutations in the dystrophin gene that cause Duchenne muscular dystrophy.”
About the Study
The study was supported, in part, by Exonics Therapeutics Inc. and grants from the National Institutes of Health, the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, and the Robert A. Welch Foundation.
Dr. Olson’s team collaborated with Professor Richard Piercy and his group at the RVC. The RVC’s canine colony program was supported by grants from the Wellcome Trust, Muscular Dystrophy UK, and Duchenne Ireland.
Disclosure statements: Dr. Eric Olson is a scientific co-founder of, and consultant for, Exonics Therapeutics, and has license and investment interests with the company. Dr. Leonela Amoasii is a consultant for Exonics Therapeutics and is listed as co-inventor, along with Dr. Olson, of the strategy presented in the study.
The study includes other disclosures.
About Exonics Therapeutics
Exonics Therapeutics is developing gene editing therapies to treat patients with Duchenne muscular dystrophy and other severe genetic neuromuscular diseases. In multiple Duchenne preclinical models, Exonics has used SingleCut CRISPR to genetically repair and restore dystrophin, the key protein missing in children with Duchenne. Exonics is initially focused on repairing mutations that cause Duchenne in order to develop a therapy to treat many children with the devastating disease, for which there is no cure. Exonics’ technology is licensed from UT Southwestern Medical Center and is based on the research of Eric Olson, Ph.D., Exonics’ founder and chief science advisor. Exonics is located in Cambridge, Mass. For more information, please visit www.exonicstx.com.