Gene therapy strategies for X-linked myotubular myopathy

ABSTRACT

Introduction: X-linked myotubular myopathy (XLMTM) is a severe, frequently fatal, type of congenital myopathy for which only supportive care is currently available. XLMTM is due to MTM1 mutations that lead to a deficiency in myotubularin, a lipid phosphatase. Restoring functional myotubularin expression in skeletal muscle would be the most direct approach to treat XLMTM. Recent work in gene therapy using animal models has revealed exciting, clinically meaningful results.

Areas covered: Gene therapy using skeletal muscle trophic adenoassociated virus 8 (AAV8) as a vector has shown promise to safely deliver MTM1 and restore myotubularin expression, which improves muscle function, ameliorates pathology and considerably lengthens survival over time. The XLMTM dog has provided a large animal model for these experiments, which has enhanced their value and our ability to move toward implementing gene therapy into XLMTM clinical care. An overview the progress that has been made will be provided here.

Expert opinion: A variety of approaches have been applied to treat XLMTM, but gene therapy appears to be the most efficient and direct means to safely restore myotubularin expression in XLMTM skeletal muscle. Future efforts will focus on ensuring the safety of gene therapy vectors while developing clinically relevant dosing regimens.

KEYWORDS:

• Adenoassociated virus
• gene therapy
• myotubularin
• MTM1
• X-linked myotubular myopathy

Article highlights

• XLMTM is a severe congenital myopathy that is due to loss of function mutations in MTM1, which leads to myotubularin deficiency.

• XLMTM patients require intense supportive care and many do not survive beyond the second year of life, therefore developing treatments that directly address the myotubularin deficiency underlying the myopathy in these patients is urgently needed.

• A number of different approaches have been studied to treat XLMTM, but gene therapy appears to be the most efficient means to directly restore myotubularin expression in XLMTM skeletal muscle and treat the underlying myotubularin deficiency.

• The AAV8-MTM1 gene therapy vector is safe and clinically effective over time in the XLMTM dog, a large animal model of XLMTM.

• Future efforts should include designing and executing clinical trials that focus on ensuring the safety of gene therapy vectors, while devising clinically relevant and effective dosing regimens.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded