Danon disease is a very rare, life-threatening condition where the fundamental biological process of removing and recycling proteins does not work. This impairment results in dysfunction of the heart, skeletal muscle, neurologic system, eyes, and liver. Most patients die or require heart transplants by the third decade of life.

In a new study published in Science Translational Medicine, researchers identified a novel way to treat Danon disease using gene therapy.

"Heart transplant is not always available for patients, and does not treat the other organs affected in Danon disease," said the principal investigator of the study. "We knew we needed to find therapies specifically designed to address the underlying cause."

Danon disease is a result of mutations in the gene LAMP2. For nearly a decade, the  team of researchers have been working to determine whether gene therapy could provide a new treatment approach. Gene therapy involves either replacing or repairing a gene that causes a medical problem or adding genes to help the body treat disease. In this case the team focused on adding a specially designed gene that restores LAMP2 function, resulting in improved cardiac and liver function.

LAMP2 has three isoforms: LAMP2A, LAMP2B, and LAMP2C. LAMP2B is the predominant isoform expressed in cardiomyocytes. This study evaluates the efficacy of human LAMP2B gene transfer using a recombinant adeno-associated virus 9 carrying human LAMP2B (AAV9.LAMP2B) in a Lamp2 knockout (KO) mouse, a DD model.

AAV9.LAMP2B was intravenously injected into 2- and 6-month-old Lamp2 KO male mice to assess efficacy in adolescent and adult phenotypes. Lamp2 KO mice receiving AAV9.LAMP2B demonstrated dose-dependent restoration of human LAMP2B protein in the heart, liver, and skeletal muscle tissue. Impaired autophagic flux, evidenced by increased LC3-II, was abrogated by LAMP2B gene transfer in all tissues in both cohorts. Cardiac function was also improved, and transaminases were reduced in AAV9.LAMP2B-treated KO mice, indicating favorable effects on the heart and liver.

Survival was also higher in the older cohort receiving high vector doses. No anti-LAMP2 antibodies were detected in mice that received AAV9.LAMP2B.

Danon disease is more common in males, and symptoms begin in early childhood or adolescence. "In many cases, the condition is inherited by a parent, typically the mother. We believe Danon disease is actually more common than we think, but it is often misdiagnosed," said the author. "By utilizing gene therapy, we were able to identify a possible new treatment approach other than a heart transplant. This study is a significant step for patients with Danon disease."

Prior studies in Adler's lab have focused on using a patient's skin cells to create stem cells. These stem cells were used to create a heart model, allowing researchers to study Danon disease at the cellular level. The approach has provided new insight into the disease's pathology and led to the idea of using gene therapy. "Our work is also proof that using stem cells to model diseases has great potential for helping develop new medicines," said the author.

The next step, said the author, is testing in patients with Danon disease. A Phase I clinical trial for safety and efficacy has begun. "This is the first trial using gene therapy to treat a genetic cardiac disorder and three patients are currently being treated, which means we're that much closer to finding a cure for this terrible disease, and may be able to use similar methods to treat other diseases.

https://stm.sciencemag.org/content/12/535/eaax1744