Sarepta, Broad Institute Strike Licensing Agreement for New Class of AAV Vectors for Gene Therapy


MyoAAV was shown to deliver 25 to 50 times greater gene expression in multiple skeletal muscles compared with natural AAV serotypes.

A licensing agreement has been executed between Sarepta Therapeutics and the Broad Institute of MIT and Harvard (Broad Institute) for Sarepta’s MyoAAV, a new group of adeno-associated viruses (AAV) for use in the treatment of Duchenne muscular dystrophy (DMD) and 4 other neuromuscular and cardiac indications.1 The agreement follows progress on Sarepta’s sponsored research agreement on the MyoAAV program, in which Sarepta confirmed earlier published research from Broad Institute.

In preclinical study data that compared MyoAAV to natural AAV serotypes in non-human primates (NHPs), MyoAAV was shown to deliver 25 to 50 times greater gene expression in multiple skeletal muscles and 10 to 15 times greater gene expression in cardiac muscle. It was also observed that MyoAAV reduced delivery to the liver by 50% and had lower accumulation in the liver.

“Research published by Broad Institute, and so far corroborated by Sarepta’s own internal research, reinforces the potential of MyoAAV as a breakthrough next-generation approach in genetic medicine delivery,” Doug Ingram, president and chief executive officer, Sarepta, said in a statement.1 “The significantly improved efficiency of MyoAAV may unlock the ability to effectively deliver genetic medicine at as much as a log lower dose when compared to current AAVs, which could substantially reduce viral load and cost of goods in the future. As one of the leaders in the use of AAV-mediated genetic medicine to treat rare disease, we intend to push the science forward, and our license for MyoAAV is a quintessential example of that effort.”

The preclinical data were published in the journal Cell in 2021, and additionally showed that the MyoAAV capsid variants had conserved potency for delivery in mouse models and human primary myotubes.2 The capsids were dependent on integrin heterodimers for transduction and showed improved efficacy in mouse models of both DMD and X-linked myotubular myopathy (XLMTM). Lead author Mohammadsharif Tabebordbar, PhD, and colleagues noted that by reducing the dose needed to reach therapeutic levels, the MyoAAV capsids could lessen risks of therapy such as classical activation of complement by capsid/antibody complexes and problems resulting from transduction into liver cells. It was pointed out that evidence of liver toxicity or other adverse effects were not observed in any of the mice that received MyoAAV vectors. Furthermore, in both mouse models, restored expression of the disease-targeted proteins and significant increases in muscle strength and performance were observed. The lifespans of the XLMTM mice treated with a MyoAAV vector were drastically increased compared with those treated with AAV9 vectors and untreated mice.

However, the investigators also noted several limitations of the study.

“Despite the highly effective and selective muscle transduction by the MyoAAV class of capsids in mice and NHPs, expression of RGD-binding integrin heterodimers is not specific to muscle tissue,” Tabebordbar and colleagues wrote.2 “Although more mechanistic studies are required to investigate the downstream signaling of integrin heterodimers after binding to MyoAAV, our working hypothesis to explain the muscle selectivity of these vectors despite the broader expression profile of integrin proteins is that expression of the integrin heterodimers on the cell surface is most likely required, but not sufficient, for potent functional transduction of cells and expression of the transgene. Since AAV transduction is a multi-step process and intracellular trafficking of the capsids and nuclear entry are also critical steps, downstream integrin signaling, which may differ in different cellular contexts, could be crucial for effective functional transduction by MyoAAV class of capsids. It is also possible that the muscle-tropism of MyoAAV reflects facilitation of transduction by other, potentially muscle-specific proteins that interact with integrin heterodimers.”

Tabebordbar and colleagues pointed out that further optimization of MyoAAV for human muscle transduction could be possible and that future research with human muscle xenografts might yield better results.

Ultimately, they concluded that the MyoAAV vectors could help to accelerate the development of gene therapy approaches for a variety of human diseases.

In addition to the 5 neuromuscular and cardiac indications previously mentioned, Sarepta will have exclusive options on other potential targets.1 The news comes following other major announcements from Sarepta regarding their DMD programs. Late last month, Sarepta announced plans to submit a biologic license application for SRP-9001, an investigative gene therapy for DMD, following positive efficacy and safety results reported several weeks earlier. However, it was also announced in June that one of Sarepta’s other investigational DMD gene therapies, SRP-5051, was placed on clinical hold by the FDA related to a serious adverse event of hypomagnesemia that occurred in part B of the ongoing 2-part, phase 2 MOMENTUM clinical trial (NCT04004065).

1. Sarepta Therapeutics announces progress on the MyoAAV program and exclusive licensing agreement with the broad institute for MyoAAV next-generation capsids for rare genetic diseases. News release. Sarepta Therapeutics, Inc. August 8, 2022. 
2. Tabebordbar M, Lagerborg KA, Stanton A, et al. Directed evolution of a family of AAV capsid variants enabling potent muscle-directed gene delivery across species. Cell. 2021;184(19):4919-4938.e22.
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