Audentes Therapeutics, Inc. announced it has expanded its scientific platform and pipeline to advance vectorized antisense treatments for the treatment of Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). This approach combines the delivery power of AAV with the precision tools of antisense oligonucleotides, or ASOs, to develop potential best-in-class therapeutic candidates for these devastating neuromuscular diseases. To accelerate these promising new programs, Audentes has entered into a licensing agreement and will collaborate with Nationwide Children's Hospital, utilizing the expertise of Kevin M. Flanigan, M.D. and Nicolas S. Wein, Ph.D., two recognized leaders in the field of genetic medicines for neuromuscular diseases. 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. For the treatment of DMD, this 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 ASO therapies, whose efficacy is limited by poor biodistribution to muscle tissue 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. 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. Both AT751 and AT753 utilize the same vector construct backbone as AT702, enabling a potentially accelerated path into clinical development. With these initial programs, Audentes is targeting more than 25% of patients with DMD, and has plans to leverage its vectorized exon skipping platform to develop further product candidates to address up to 80% of DMD patients over time. In addition, Audentes and Nationwide Children's are evaluating vectorized RNA knockdown and vectorized exon skipping for myotonic dystrophy type 1 (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 ASOs. 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. Audentes plans to leverage its proprietary AAV gene therapy technology platform, consisting of end-to-end internal expertise from vector construct engineering to state-of the-art large-scale cGMP manufacturing, to rapidly advance these programs from discovery through clinical development. Internal process and analytical development, fill-finish, and QC testing capabilities complete the company's fully-integrated approach to production and release of product candidates for clinical and commercial use. The current 1,000-liter scale manufacturing operation provides enough capacity for global commercialization of the company's lead program AT132, as well as continued clinical development of pipeline programs, and the facility is designed for expansion to include an additional 8,000 liters of production capacity.