New hope for X-linked myotubular myopathy as gene therapy clinical trial begins

gene therapy myotubular myopathy

Boys born with X-linked myotubular myopathy (XLMTM) face a grim prognosis. Extreme muscle weakness leaves many ventilator-dependent from birth, and most infants need feeding tubes. About half pass away before 18 months of age.

Last week, the biotechnology company Audentes Therapeutics announced the dosing of the first patient in a gene-therapy clinical trial — 21 years after the MTM1 gene was first cloned.

Hopes are high. Gene therapy has already shown striking benefits in dogs with XLMTM in studies co-authored by Alan Beggs, PhD, director of the Manton Center for Orphan Disease Research at Boston Children’s Hospital, and colleagues at Généthon and the University of Washington. In the most recent study, 10-week-old Labrador retrievers already showing signs of the disease showed improvements in breathing, limb strength and walking gait after a single dose of the gene therapy vector.

gene therapy myotubular myopathy NibsNibs, a carrier of XLMTM whose descendants took part in preclinical gene therapy studies. Read her story.

The open-label Phase I/II trial, ASPIRO, will evaluate the safety and preliminary efficacy of a single dose of AT132, the viral vector carrying a functional copy of the MTM1 gene. Measures will include respiratory and motor function parameters and, as a secondary endpoint, muscle biopsy. The goal is to enroll 12 children under five years of age and test three different doses. Preliminary data are expected to be available in the fourth quarter of 2017, according to Audentes.

Setting a benchmark for XLMTM

In the meantime, a companion natural history study of the disease, INCEPTUS, and a chart-review study, RECENSUS, are helping define the disease burden of XLMTM more precisely, necessary groundwork for evaluating the effects of gene therapy.

RECENSUS announced initial data in March, based on 112 boys with XLMTM. Among the findings: Babies with the disease spent 35 percent of their time hospitalized and underwent an average of 3.7 operations. Forty-eight percent needed around-the-clock ventilation.

“RECENSUS has established one of the largest data sets of XLMTM in the world, and this analysis makes a vital contribution to our understanding of this terrible disease,” said Beggs, the study’s principal investigator, said in a news release.

On the positive side, as awareness of XLMTM has increased, diagnoses are being made earlier — at a mean of 4.4 months of age from 2011-2014, as compared with almost 3 years in the late 1990s. Results of INCEPTUS are expected to be published soon.

More about myotubular myopathy research on Vector.