IN BRIEF

Gene Therapy Continues to Show Promise for Limb-Girdle Muscular Dystrophy

June 13, 2017

Louise Rodino-Klapac, PhD, principal investigator in the Center for Gene Therapy, shares an update on the advancement of LGMD2E gene therapy to clinical studies.

Each of the approximately 20 subtypes of Limb-girdle muscular dystrophy (LGMD) is a rare disease requiring unique therapy. While the epidemiology and symptoms for each subtype maybe similar, the mutations and molecular processes governing the disease process are unique to each subtype.

Limb-girdle muscular dystrophy type 2E (LGMD2E) is a form of muscular dystrophy that shares several typical, yet often severe, characteristics of other LGMD subtypes, including widespread progressive muscle wasting, initial pelvic and shoulder girdle weakness, degrees of proximal weakness and evidence of Gower’s maneuvers. While the spectrum of clinical presentation is heterogeneous, in more severe Duchenne Muscular Dystrophy (DMD)-like cases, symptoms onset in early childhood with increasingly difficult mobility and eventual loss of ambulation in adolescence. The incidence worldwide is 1/200,000 to 1/350,000. Unlike DMD, LGMD affects males and females equally.

Because of the extensive musculoskeletal involvement, joint contractures and kyphoscoliosis of the thoracic spine can occur, leading to compromised diaphragm and lung function when combined with the degenerating diaphragm.

Additionally, more than 50 percent of LGMD2E patients suffer from cardiac dysfunction.

LGMD2E is the result of mutations in the beta-sarcoglycan gene that lead to loss of functional protein and concurrent loss of other structural components of the sarcolemmal-stabilizing dystrophin-associated protein complex.

Gene therapy, particularly AAV-mediated, has shown great promise in the treatment of muscular dystrophies and other neuromuscular diseases. At Nationwide Children’s, we are at the global forefront of muscular dystrophy gene and therapy discovery and clinical translation.

Recently, our lab published the results of a preclinical study that provides the rationale for clinical trial. In our study, animal models were injected with a new scAAVrh74.MHCK7.hSGCB transgene cassette through the tail vein. We noted improvement in histopathology and 98.1 percent transgene expression across all muscles. Additional effects included:

  • Creatine kinase levels decreased by 85.5 percent
  • Diaphragm force production increased 94.4 percent
  • Kyphoscoliosis of the thoracic spine decreased by 48.1 percent
  • Overall ambulation increased by 57 percent
  • Vertical rearing increased by 132 percent

Equally as important, no adverse effects were noted in our control group of healthy models who also received the injection.

To bring this therapy to trial, and others for LGMD to patients, a start-up company, Myonexus Therapeutics, was created around technology licensed from Nationwide Children’s Hospital. Myonexus Therapeutics is a clinical stage gene therapy company developing first-ever treatments for LGMD types 2D, 2B, 2E, 2L and 2C. Clinical trials are underway for types 2D and 2B. We have obtained IND approval for LGMD2E for an intravenous phase 1 trial at Nationwide Children’s Hospital. If successful, trials will expand to other sites for phase 2.