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Exonics Therapeutics Shows Restoral of Dystrophin Expression in Canine Model of Duchenne Muscular Dystrophy

First study of Exonics’ gene editing technology in large mammals supports clinical advancement (Image: Exonics Therapeutics).

~ First study of Exonics Therapeutics’ gene editing technology in large mammals supports clinical advancement ~

Duchenne muscular dystrophy is a progressive, irreversible and ultimately fatal disorder characterized by progressive muscle degeneration and weakness. It predominantly affects boys, with symptoms that usually manifest between age three and five and affecting about one in every 3,500 boys worldwide, according to the National Organization for Rare Disorders. The disease is caused by mutations in the dystrophin gene, which result in the absence or near-absence of dystrophin protein. Dystrophin normally works to strengthen muscle fibers and protect them from daily wear and tear. Without functioning dystrophin and certain associated proteins, muscles suffer excessive damage from otherwise normal daily activities and are left unable to regenerate. Until relatively recently, Duchenne patients usually did not survive much beyond their teen years, according to the Muscular Dystrophy Association, but advances in cardiac, respiratory and—most recently—genetic science have begun to extend life expectancies.

Results from a preclinical study were published online in the journal Science last week showing that Exonics Therapeutics‘ gene editing technology restored in vivo dystrophin expression in a canine model of Duchenne. The study evaluated delivery of CRISPR/Cas9 gene editing components in canines with a naturally-occurring mutation that leads to deletion of exon (gene segment) 50, which is among the most common single exon deletions in the dystrophin gene that causes Duchenne in humans. Treated canines showed a restoral of dystrophin expression of up to 90% 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% of normal levels. Notably, no off-target effects of gene editing were detected in the study.

Source: Exonics Therapeutics

The study was supported, in part, by Exonics Therapeutics and grants from the National Institutes of Health, the Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center, and the Robert A. Welch Foundation. It was conducted in collaboration with UT Southwestern Medical Center in Dallas and the Royal Veterinary College in London, with initial support provided by CureDuchenne Ventures.

Exonics’ SingleCut CRISPR gene editing technology:

  • Uses cell’s natural mechanisms for gene repair to induce normal expression of dystrophin
  • Single cut makes minimum genomic modification, at precise location
  • Targets specific cell types to repair: skeletal muscle, cardiac, diaphragm
  • Durable effect after one administration
  • Treats underlying cause of neuromuscular genetic diseases

The technology is licensed from UT Southwestern Medical Center and is based on the research of Eric Olson, PhD, Exonics’ founder and chief science advisor.

The encouraging findings from this preliminary study using Exonics’ SingleCut CRISPR approach are very significant as a model for future translational studies. 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.

– Eric Olson, PhD.

The company raised $40 million from The Column Group in its Series A round in November 2017. CEO John Ripple previously served as CEO of Ensemble Therapeutics, Permeon Biologics, Virdante Pharmaceuticals (acquired by Momenta Pharmaceuticals), and Syntonix Pharmaceuticals (acquired by Biogen). He also founded Ripple Biotech, a strategic advisory firm.

In addition to Mr. Ripple and Dr. Olson, Exonics’ board of directors includes Roger M. Perlmutter, MD, PhD, JJ Kang, PhD and David Goeddel, PhD. Dr. Perlmutter is EVP and president of Merck Research Laboratories, Merck’s MRK global R&D organization, and was previously EVP and head of R&D at Amgen AMGN. Dr. Kang is a Principal at The Column Group and president and board member of Tenaya Therapeutics. Dr. Goeddel was the first scientist at Genentech, whose pioneering work in gene cloning and expression of human proteins was the basis for five marketed therapeutics, including human insulin, human growth hormone, interferon-alpha, interferon-gamma, and tissue plasminogen activator.

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. 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.

– John Ripple, CEO, Exonics.

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