Rare Daily Staff

Audentes Therapeutics said it has expanded its scientific platform and pipeline to advance experimental treatments for the treatment of Duchenne muscular dystrophy and myotonic dystrophy type 1 that use viral vectors to deliver antisense oligonucleotides to target these rare neuromuscular diseases.

The company said it has entered into a licensing and collaboration agreement with Nationwide Children’s Hospital to accelerate the new programs.

“We see tremendous potential in combining AAV with validated oligonucleotide-based approaches to treat diseases that are not amenable to traditional AAV-based gene replacement,” said Matthew Patterson, chairman and CEO of Audentes. “We believe this approach, combined with our in-house large-scale cGMP manufacturing capability, can deliver best-in-class therapies for the treatment of Duchenne muscular dystrophy and myotonic dystrophy.”

Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy in children. DMD is caused by mutations in the dystrophin gene, which encodes the protein dystrophin, a structural protein involved in maintaining muscle cell integrity. Patients with DMD typically develop muscle weakness in the early years of life and become wheelchair-bound in their early teens.  As the disease progresses, patients typically develop respiratory, orthopedic, and cardiac complications. Few individuals with DMD live beyond their thirties.  There is no cure for the condition, and for most patients, there are no satisfactory symptomatic or disease-modifying treatments.

Audentes and Nationwide Children’s are collaborating to develop AT702, an AAV-antisense candidate designed to induce exon 2 skipping for DMD with duplications of exon 2 and mutations in exons 1-5 of the dystrophin gene. 

Vectorized exon skipping uses an AAV vector to deliver an antisense sequence designed to induce cells to skip over faulty or misaligned sections of genetic code, leading to the expression of a more complete, functional protein. The company said the approach has the potential to provide significant advantages over microdystrophin gene replacement strategies that produce a substantially truncated protein, which may limit the degree and durability of disease correction, as well as existing antisense oligonucleotides therapies, whose efficacy is limited by poor biodistribution to muscle tissue.

In preclinical studies of mice with exon 2 duplications, AT702 demonstrated robust proof-of-concept with dose-dependent increases in production of wild type or near-wild type length dystrophin protein and improvements in muscle function. Audentes is currently conducting additional preclinical work and expects to commence a Phase 1/2 study at Nationwide Children’s in the fourth quarter of 2019.

Separate from the Nationwide Children’s collaboration, Audentes is also conducting preclinical work to advance AT751 and AT753, additional vectorized exon skipping candidates, to treat DMD patients with genotypes amenable to exon 51 and exon 53 skipping. With these initial programs, Audentes is targeting more than 25 percent of patients with DMD and has plans to leverage its vectorized exon skipping platform to develop further product candidates to address up to 80 percent of DMD patients over time.

Myotonic dystrophy type 1 (DM1), is a rare, neuromuscular disease that affects multiple organ systems, and is characterized primarily by myotonia and progressive muscle wasting and weakness. DM1 has several forms that range in age of presentation and severity, including congenital, infantile, juvenile, and adult (classic). The disease is caused by a mutation in the dystrophia myotonica-protein kinase (DMPK) gene.  Patients with DM1 experience reduced quality of life and shortened life expectancy. There are no disease modifying therapies approved for DM1.

Audentes and Nationwide Children’s are evaluating vectorized RNA knockdown and vectorized exon skipping for DM1. Both approaches are designed to prevent the accumulation of toxic dystrophia myotonica-protein kinase (DMPK) RNA in affected cells, thereby restoring normal cellular function. RNA knockdown and exon skipping have both been clinically validated in studies with antisense oligonucleotides. As with DMD, combining these approaches with AAV delivery is expected to overcome the biodistribution limitations of ASO-based therapies. 

Preclinical studies are underway, and Audentes expects an IND for the selected product candidate, AT466, to be filed in 2020.

Photo: Matthew Patterson, chairman and CEO of Audentes

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