Children born with X-linked myotubular myopathy, which affects about 1 in 50,000 male births, have very weak skeletal muscles, causing them to present as “floppy,” with severe respiratory difficulties. Survival beyond birth requires intensive support, often including tube feeding and mechanical ventilation, but effective therapy is not available for patients, and most die in childhood.
Alan Beggs, PhD, director of The Manton Center for Orphan Disease Research at Boston Children’s, and co-senior author on the paper, has studied the mutated gene, known as MTM1, for many years and previously showed that replacing the missing myotubularin protein (a result of the mutation) improved MTM muscles’ ability to contract.
Based on this research and pioneer work in a mouse model of the disease, performed by Anna Buj-Bello, PhD, at Généthon since 2009, Beggs and Buj-Bello joined Martin K. Childers, DO, PhD, of the University of Washington, to test gene therapy using an engineered adenovirus (AAV) vector, created by Généthon, to carry the replacement MTM1 gene. The team used two animal models: mice with an engineered MTM1 mutation and dogs carrying a naturally occurring MTM1 gene mutation. These animals appear very weak with shortened lifespans, similar to patients with myotubular myopathy.
The researchers found that both mice and dogs responded to a single intravascular injection of AAV with robust improvement in muscle strength and function, corrected muscle structure at the microscopic level and prolonged life. No toxic or immune response was observed in the dogs. These results demonstrate the efficacy of gene replacement therapy for myotubular myopathy in animal models and pave the way to a clinical trial in patients.
“The implications of the preclinical findings are extraordinary for inherited muscular diseases,” said Childers, who was co-principal investigator of the study with Buj-Bello and Beggs. “Two of our dogs treated with AAV gene therapy appear almost normal with little, if any evidence, even microscopically, of the disease caused by XLMTM.”
"These results are the culmination of four years of research and show how gene therapy is effective for this genetic muscle disease,” said Buj-Bello.
"The dramatic long-term improvement in both mice and dogs following only a single dose of gene therapy is extremely exciting,” adds Beggs. “It provides us with the necessary information to begin planning the first clinical trials of a treatment for this deadly condition.”
Research by the Beggs team was funded by the National Institutes of Health (grants P50 NS040828, R01 AR044345 and K08 AR059750), the Anderson Family Foundation and the Joshua Frase Foundation, a long-standing supporter. For further background on the research, read this two-part blog series.
About Boston Children's Hospital
Boston Children’s Hospital is home to the world’s largest research enterprise based at a pediatric medical center, where its discoveries have benefited both children and adults since 1869. More than 1,100 scientists, including seven members of the National Academy of Sciences, 14 members of the Institute of Medicine and 14 members of the Howard Hughes Medical Institute comprise Boston Children’s research community. Founded as a 20-bed hospital for children, Boston Children’s today is a 395-bed comprehensive center for pediatric and adolescent health care. Boston Children’s is also the primary pediatric teaching affiliate of Harvard Medical School. For more information about research and clinical innovation at Boston Children’s, visit: http://vectorblog.org.