Gene Therapy for Danon Disease

Danon disease is a rare genetic disorder that affects several tissues and organ systems in the body. It is a type of ​lysosomal storage disease (LSD). 

Lysomal storage diseases occur when the body doesn’t have the necessary protein cells to properly metabolize and recycle waste (an intracellular process called autophagy). When this protein is missing, there is an unhealthy buildup of material in cells that leads to Danon disease.

The most common symptoms of Danon disease are:

• Thickening/weakening of the heart muscle (also known as severe hypertrophic cardiomyopathy)
• Weakening of arm and leg muscles; poor muscle tone (also known as skeletal muscular myopathy)
• Cognitive delays
• Vision impairment, typically related to the retinas

LAMP-2 is the gene responsible for telling the body how to produce proteins that metabolize and recycle waste. When LAMP-2 mutates (or changes) it can cause Danon disease. 

The X chromosome carries LAMP-2, which means that boys (who have only one X chromosome) often have a more severe version of the disease than girls (who have two X chromosomes, which may dilute the effect of a single mutated gene).

Clinical trials are in process that use gene therapy to fight Danon disease. 

In a phase 1 trial conducted at Children's Hospital of Philadelphia (CHOP), six patients (four adults and two children) received a one-time intravenous infusion of RP-A501. RP-A501 is an experimental adeno-associated virus (AAV)-based gene therapy, which replaces the missing or nonworking LAMP-2 gene with a normal LAMP-2 gene. Patients also received immunosuppressants for several months. This prevented their immune systems from reacting negatively to the genetic infusion.

Evaluations of phase 1 trial participants continue, but initial results show promise. CHOP doctors have followed the first adult participants for three years post-infusion, and the child participants for nine to 18 months post-infusion. In cases where patients were given immunosuppressants, Danon disease symptoms showed improvement within three to six months.

Phase 2 of a clinical trial at CHOP is in development.

While there are currently no FDA-approved treatments for Danon disease, affected children come to the Cardiac Center at CHOP to have their symptoms managed.

Joseph Rossano, MD, MS, Chief of Cardiology and the center’s Co-Executive Director, is one of our leading experts in evaluating the treatment and outcomes of pediatric cardiomyopathy and heart failure. Dr. Rossano aims to improve the lives of children with heart disease through clinical care, research, advocacy and education.

To help manage the disease, heart failure medications are sometimes used to treat cardiac symptoms, but these are not effective in the long term. Patients with severe forms of the disease rarely survive adolescence or early adulthood without a heart transplant. Research in this field is critical, and Dr. Rossano and other CHOP experts are working tirelessly to find new options for children with Danon disease. 

FDA-approved gene therapies for Danon disease

Clinical trials for gene therapy are ongoing, at CHOP and elsewhere. There are currently no FDA-approved gene therapies for Danon disease.

Clinical trials for Danon disease

There are currently active gene therapy clinical trials for Danon disease: 

• Check back for an up-to-date list of trials

Phase 1 of the RP-A501 clinical trial at CHOP is complete, and findings are being analyzed. The trial studied four adults and two children; CHOP was the first study site to include children in the study sample. CHOP doctors are currently developing plans for a phase 2 trial.