Children's Hospital of Philadelphia Researchers Announce Promising Results from First-of-its-Kind, Multicenter, Phase 1 Gene Therapy Trial for Danon Disease

Results show potential for gene therapy to improve long-term cardiac outcomes

PHILADELPHIA, Nov. 18, 2024 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) announced encouraging results from the first ever gene therapy trial for Danon disease (DD), a rare, X-linked heart condition caused by a single gene mutation. The phase 1 trial was a collaboration between CHOP and the University of California, San Diego Medical Center, the University of Colorado, Anschutz Medical Center, Boston Children's Hospital and Rocket Pharmaceuticals. The data on the results of the RP-A501 Phase 1 trial, presented at a late breaking session today at the American Heart Association Scientific Sessions 2024 in Chicago, were also published in the New England Journal of Medicine.

Danon disease (DD) is a rare genetic disorder that affects several tissues and organ systems in the body. It is a type of lysosomal storage disease (LSD), 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 leads to DD. Common symptoms include thickening or 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 and vision impairment.

As a leader in innovative cell and gene therapies, pediatric cardiac treatment and robust research, participating in these groundbreaking collaborations was a natural progression for CHOP.

"There's an urgent need for new therapies for young patients with Danon disease," said Joseph Rossano, MD, MS, FAAP, FACC, Chief of the Division of Cardiology at CHOP and one of the principal investigators in the RP-A501 Phase 1 trial. "Our results suggest gene therapy has the potential to improve long-term cardiac outcomes in this highly aggressive and fatal genetic disorder." 

In this study, sponsored by Rocket Pharmaceuticals, Inc., seven male patients ages 11-21 received a single 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-2B gene. Patients also received immunosuppressants for several months. Of the study site participants, CHOP administered gene therapy solely to pediatric patients, while the University of California, San Diego treated both pediatric and adult patients.

LAMP-2 is the gene responsible for telling the body how to produce proteins that metabolize and recycle waste. Mutations of LAMP-2 can cause DD, which is carried on the X chromosome. Researchers focused on young male patients because boys typically have a more severe version of the disease due to having one X chromosome compared with girls who have two, which can dilute the effect of a single mutated gene.

Overall, the researchers found that RP-A501 can arrest and reverse underlying genetic, molecular, and cellular causes of DD. Over 24-54 months of follow-up, the patients' symptoms significantly improved, suggesting that the therapy has the potential to help patients achieve long-term positive outcomes. In CHOP's cohort, the researchers observed that children taking immunosuppressants experienced less muscle weakness in three to six-months.

Based on the positive results, a global Phase 2 registrational-enabling study assessing the safety and efficacy in male patients with DD is currently underway.

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

Greenberg et al. "Phase 1 Study of AAV9.LAMP2B Gene Therapy in Danon Disease." N Engl J Med Online November 18, 2024. DOI: 10.1056/NEJMoa2412392.

About Children's Hospital of Philadelphia: 
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

Contact: Natalie Solimeo
Children's Hospital of Philadelphia
267-426-6246
[email protected]

SOURCE Children's Hospital of Philadelphia