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Cell & Gene Therapy Insights

Cell & Gene Therapy Insights

Audentes and Nationwide Children’s to collaborate over AAV-antisense technology

Audentes Therapeutics has announced its plan to expand its scientific platform by combining antisense oligonucleotide technology with adeno-associated virus (AAV)-based delivery system to treat Duchenne muscular dystrophy (DMD) and myotonic dystrophy type 1 (DM1). The company is developing programs across three modalities: gene replacement, vectorized exon skipping and vectorized RNA knockdown.

San Francisco-based Audentes is a private development stage biotechnology company developing new therapies for patients with rare muscle diseases using AAV gene therapy technology. To do this, Audentes has entered into a licensing agreement with Nationwide Children’s Hospital and will collaborate with Dr Kevin Flanigan and Dr Nicolas Wein, two leading researchers in the field of genetic medicines for neuromuscular diseases.

The technology will use AAV vectors to deliver antisense oligonucleotides to cells. The oligonucleotides are 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 approach is believed to have more advantages over microdystrophin gene replacement therapy for DMD where a truncated protein is expressed which could affect the efficiency of disease correction, as well as existing antisense oligonucleotide therapies.

AT702, the first AAV-antisense product candidate which will be developed under the collaboration is designed to induce exon 2 skipping for DMD with duplications of exon 2 and mutations in exons 1-5 of the dystrophin gene. Data obtained from preclinical mice studies have shown a dose-dependent increase in production of functional dystrophin protein and muscle function after administering AT702. Audentes is currently conducting additional preclinical work and expects to commence a Phase 1/2 study at Nationwide Children’s towards the end of 2019.

Preclinical work is also being conducted to advance two other product candidates, AT751 and AT753 to treat DMD patients with genotypes amenable to exon 51 and exon 53 skipping. These products use the same vector construct backbone as AT702, which could potentially accelerate their path to clinical development. Using the 3 product candidates, Audentes is hoping to target more than 25% of patients with DMD, and has plans to expand the platform to treat up to 80% of DMD patients eventually.

In addition to DMD, Audentes and Nationwide Children’s will work together for developing therapies for DM1 as well. Two approaches, vectorized RNA knockdown and vectorized exon skipping, will be tested to prevent the accumulation of toxic dystrophia myotonica-protein kinase RNA in affected cells, thereby restoring normal cellular function. Preclinical studies are underway, and Audentes expects to file IND application for the treatment in 2020.

From vector construct engineering to large-scale cGMP manufacturing, Audentes has the expertise and capability to advance these programs from discovery through clinical development.

Matthew R. Patterson, CEO of Audentes commented: “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. 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.”

Source: Audentes Therapeutics Licenses Muscular Dystrophy Tech From Nationwide Children’s Hospital; Press Release

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