Can Gene Therapy Improve Long-term Cardiac Outcomes for Patients with Danon Disease?

Early Phase 1 trial results show potential for gene therapy to improve long-term cardiac outcomes for patients with Danon disease.

The Findings

In the first gene therapy trial for Danon disease, a rare X-linked heart condition caused by a gene mutation, researchers found that a single infusion of an investigational adeno-associated virus (AAV)-based gene therapy, known as RP-A501, can help treat and potentially reverse underlying genetic, molecular, and cellular causes of Danon disease.

Findings from the Phase 1 study suggest that RP-A501 appeared to be generally safe and was associated with cardiac LAMP2 protein expression and evidence of clinical improvement over a period of 24 to 54 months. LAMP2 is the gene responsible for telling the body how to produce proteins that metabolize and recycle waste. When LAMP2 mutates, it can cause Danon disease. RP-A501 replaced the mutated gene that leads to Danon disease.

All patients were alive, and all serious adverse events resolved. One patient had worsening of heart failure at baseline due to Danon disease and received a transplant five months after receiving the therapy, therefore some of the efficacy results are not inclusive of this patient.

Heart failure symptoms were stabilized or reduced, and there was stabilization of or improvement in cardiac structure and function. Other key outcomes revealed sustained reduction or stabilization of symptoms and a favorable immunologic response to RP-A501. Early efficacy signals included a possible lower incidence of end-stage heart failure and improvement of overall survival rates.

Why It Matters

No FDA-approved treatments for Danon disease exist, so new therapies for young patients are needed urgently. The preliminary results suggest gene therapy has the potential to improve long-term cardiac outcomes in this rare — affecting between 15,000 and 30,000 people in the United State and Europe — yet highly aggressive and fatal genetic disorder.

Danon disease affects several tissues and organ systems in the body. It is a type of lysosomal storage disease, which occurs when the body does not have the necessary protein cells to properly metabolize and recycle waste. When this type of protein is missing, there is an unhealthy buildup of material in cells that can lead to Danon disease.

One of the most common symptoms of the disease is cardiac hypertrophy, a thickening or weakening of the heart muscle, which makes it difficult for the heart to pump blood. Other symptoms include weakening of arm and leg muscles, poor muscle tone, cognitive delays, and vision impairment.

The X chromosome carries LAMP2, which means boys, who have only one X chromosome, often have a more severe version of the disease and earlier onset of symptoms than girls. In male patients, the predominant phenotype is progressive cardiac hypertrophy, cardiac dysfunction, and early death.

Who Conducted the Study

The Phase 1 trial was a collaboration between CHOP, University of California San Diego Medical Center, University of Colorado Anschutz Medical Campus, Boston Children's Hospital, and Rocket Pharmaceuticals. Joseph Rossano, MD, MS, Chief of the Division of Cardiology at CHOP, was one of the principal investigators and senior author of the study.

How They Did It

Seven male patients with a confirmed Danon disease diagnosis and LAMP2 mutation received a single infusion of RP-A501. Five of the patients were 15 years of age or older, and two were between 11 and 14 years of age. RP-A501 replaced the missing or nonworking LAMP2 gene with a normal LAMP2B gene. The therapy was administered as a single IV infusion. Patients also received immunosuppressants (prednisone, tacrolimus or sirolimus, and rituximab) for several months. Of the study site participants, CHOP administered RP-A501 solely to pediatric patients.

Quick Thoughts

"CHOP's extensive experience in gene therapy and cardiac research not only works toward the best outcomes for these patients but also brings hope for improved health and brighter futures," Dr. Rossano said.

What's Next

Already underway is a Phase 2 trial that will evaluate the safety and efficacy of the investigational gene therapy RP-A501 in male participants with Danon disease age 8 and older.

Where the Study Was Published

The study was featured in New England Journal of Medicine and was sponsored by Rocket Pharmaceuticals.