Gene therapy for myotubular myopathy

A new gene therapy treatment has had striking results in nine boys born with myotubular myopathy (MTM), a rare disease that causes extreme muscle weakness often from birth. All of the boys have better neuromuscular function, most can sit on their own, and four are now breathing without ventilators. As videos of their improvements were shown here on 1 May at the annual meeting of the American Society of Gene & Cell Therapy (ASGCT), the audience broke out in applause. The results, the first of their kind for this rare disease, cap a year of early signs of success in using gene therapy for inherited muscle diseases.

As far as muscle function is concerned, the boys “have gone from nothing to something,” says principal investigator Perry Shieh, a neurologist at the University of California, Los Angeles. “Time will tell how much that something will be.”

The patients in the new study have X-linked MTM, caused by a defect in a gene called MTM1 that encodes an enzyme, myotubularin. Skeletal muscles need the enzyme to develop and function. Boys with the disease have low muscle tone and, in many cases, can barely breathe or move on their own; most require a ventilator and feeding tube. Half of patients die by 18 months, and few live past age 10.

In the trial, sponsored by Audentes Therapeutics, a gene therapy company in San Francisco, California, nine boys between 8 months and 6 years old with X-linked MTM received an intravenous (IV) infusion of many trillions of particles of a harmless virus, called an adeno-associated virus. The viruses were designed to carry a good copy of the MTM1 gene into the boys’ muscle cells. The gene, a free-floating piece of DNA, could then trigger the cell’s proteinmaking machinery to produce myotubularin. Three patients had serious side effects that may have been related to the therapy, such as heart inflammation, but all were treatable.

Biopsies showed that 48 weeks after the first six boys received treatment, their leg muscle cells that previously had virtually no myotubularin were making, on average, 85% of the normal amount, Shieh reported yesterday. The boys’ abnormally small muscle fibers had grown larger. Four can now sit up without help, and three are taking steps with assistance; although still receiving nutrition through a feeding tube, several have started to eat food. And some can vocalize sounds for the first time, Shieh says.

In one set of before-and-after videos, a 1-year-old boy lay passively on an examining table; 48 weeks after his treatment, he could stand and take steps with help. In another, a child who wobbled and needed help to sit up later sat alone and reached out to grab a toy. Three children treated with a higher dose are showing similar motor function gains after 6 months, along with faster changes in their muscle cells and up to double the amount of myotubularin that a healthy child’s cells make, Shieh reported.

“They’re getting great results,” says gene therapy researcher and ASGCT president Michele Calos of Stanford University in Palo Alto, California, who chaired a symposium of the meeting’s top abstracts, where Shieh presented. And in theory, those results could last: Because muscle cells don’t normally divide, the extra myotubularin could keep the boys’ muscles working for years to come. Dogs with a milder form of MTM that received the same therapy and gained the ability to run are still doing fine years later, Shieh notes.

The treatment will be tested in more children before Audentes seeks approval from the U.S. Food and Drug Administration (FDA). Meanwhile, another IV gene therapy, for a rare genetic disease called spinal muscular atrophy that led to dramatic improvements in 15 children is expected to soon become the second FDA-approved gene therapy for an inherited disorder. (The first was gene therapy for an inherited form of blindness in late 2017.)

https://www.sciencemag.org/news/2019/05/boys-rare-muscle-disease-are-breathing-their-own-thanks-gene-therapy

Courtesy of Doximity

652 - ASPIRO Phase 1/2 Gene Therapy Trial In XLinked Myotubular Myopathy (XLMTM): Update on Preliminary Safety and Efficacy Findings

Author Block: Perry B. Shieh1, Nancy Kuntz, Barbara Smith, Carsten G. Bönnemann, James J. Dowling, Michael W. Lawlor, Wolfgang Müller-Felber, Mo Noursalehi, Salvador Rico, Laurent Servais, Suyash Prasad Neurology, UCLA Medical Center, Los Angeles, CA, Ann & Robert H Lurie Children's Hospital of Chicago, Chicago, IL,University of Florida, Gainesville, FL, NIH Porter Neuroscience Research Center, Bethesda, MD,Hospital for Sick Children, Toronto, ON, Canada,Medical College of Wisconsin, Milwaukee, WI,Klinikum der Universität München, Munich, Germany,Audentes Therapeutics, San Francisco, CA,Hôpital Armand Trousseau, Paris, France

Background: XLMTM is a rare monogenic disease caused by mutations in the MTM1 gene, which encodes myotubularin, a protein required for normal development and function of skeletal muscle. XLMTM is characterized by extreme muscle weakness, respiratory failure and early death. Methods: ASPIRO is an ongoing Phase 1/2 open-label, randomized, ascending dose study to evaluate the safety and efficacy of an investigational gene therapy product (AT132) in patients with XLMTM. AT132 (rAAV8- Des-hMTM1) is designed to deliver functional copies of the MTM1 gene to skeletal muscle cells. ASPIRO was designed for XLMTM pts <=5 years, randomized onto drug or delayed control, and enrolled into ascending dose cohorts to receive a single AT132 infusion.

Results: At the time of 26Sep18 data cut, safety and efficacy data from 4-48 weeks of follow-up were reported for 8 patients, including 7 patients in Cohort 1 (1x1014 vector genomes per kilogram (vg/kg); 6 treated and 1 untreated control) and the sentinel patient in Cohort 2 (3x1014 vg/kg), as well as Week 24 muscle biopsy data for the first 4 treated patients. All treated patients showed meaningful improvements in neuromuscular and respiratory function; with increased limb and trunk strength; improved velocity, coordination, and movement accuracy; and improved ability to communicate (increased loudness during vocalization and crying). In addition, there have been improvements in airway clearance, secretions management and swallowing capability, to the extent that patients are now beginning to tolerate oral food. Efficacy assessments have shown clinically meaningful improvements in both the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale and maximal inspiratory pressure (MIP) (Table). Notably, patients achieved scores close to the maximum CHOP INTEND score of 64, a level of functional performance typically achieved in a healthy child by 3-6 months of age. All patients had attained the ability to sit without support, one patient was crawling, and two patients were standing with support and making stepping movements. At 24 weeks, all patients assessed showed significant reductions in ventilator use, with three patients reaching ventilator independence. All of these improvements are clinically meaningful and inconsistent with the natural course of this disease. Muscle biopsy results were consistent with marked functional improvements, demonstrating robust tissue transduction and myotubularin expression, and considerably improved muscle fiber morphology. The safety profile of AT132 has been manageable: a total of seven serious AEs occurred, five in Patient 3 of which four were possibly or probably related to treatment. Subsequent to the data cutoff date, the remainder of Cohort 2 has been enrolled. Updated safety and efficacy data will be presented at the 2019 ASGCT Annual Congress.

http://50.23.255.131/clients/schedule_pdfs/1866/mediaid_337.pdf