Dosing begins in gene therapy trial for DMD-linked heart disease
Small US study testing treatment in men with cardiomyopathy
The first patient has been dosed as part of a Phase 1b clinical trial of AAV1.SERCA2 (SRD-003), Sardocor‘s one-time gene therapy for cardiomyopathy — a type of heart disease — associated with Duchenne muscular dystrophy (DMD-CM).
The multicenter trial, dubbed MUSIC-DMD (NCT06224660), is being conducted in collaboration with the University of Kansas Medical Center. It’s expected to enroll up to 12 men, ages 18 and older, with DMD and signs of cardiomyopathy. Enrollment is ongoing at the site in Kansas City, as well as at sites in Columbus and Cincinnati, in Ohio.
“This milestone represents a pivotal advancement in the treatment of DMD-associated cardiomyopathy,” Ronald Li, PhD, CEO and cofounder of Medera, Sardocor’s parent company, said in a company press release, which called the therapy “pioneering.”
According to the company, the needed surgery was well-tolerated by the patient, who was observed in the hospital overnight.
In DMD, mutations in the DMD gene result in little to no dystrophin, a protein that helps protect the muscles from damage caused by the stress of movement. Without sufficient dystrophin, muscle cells accumulate damage over time, which in turn drives disease symptoms.
Heart problems becoming more common in DMD
DMD affects skeletal muscles, or those attached to bones that enable movement, as well as those involved in breathing and digestion. The genetic condition can also affect the muscles of the heart, leading to cardiomyopathy, in which the heart becomes enlarged and weakened, impairing its ability to pump blood.
Due to advances in respiratory care, people with DMD today are living longer, and as a result, cardiac complications are becoming increasingly prevalent, the researchers noted. Still, current treatments for DMD-associated cardiomyopathy rely on standard therapies for heart failure, limiting their effectiveness in this patient population.
“As survival rates improve due to respiratory interventions, cardiac complications have emerged as the leading cause of mortality in DMD patients,” Li said.
In recent years, gene therapy has become a promising treatment option for DMD patients. It typically involves correcting the genetic defect underlying the disease by introducing a healthy copy of the affected gene into the patient’s cells.
Here, instead of delivering a gene encoding dystrophin, AAV1.SERCA2 provides a gene that encodes SERCA2a, a protein that regulates calcium levels within heart muscle cells. DMD-associated cardiomyopathy is marked by calcium overload in these cells, leading to progressive scarring, known medically as fibrosis, and heart failure.
Delivered directly to heart muscle cells using an adeno-associated virus, AAV1.SERCA2 is intended to restore calcium flow in patients with DMD-CM by boosting SERCA2a protein production, potentially reversing the underlying cardiomyopathy process.
As survival rates improve due to respiratory interventions, cardiac complications have emerged as the leading cause of mortality in DMD patients.
According to Pradeep Mammen, MD, the trial’s principal investigator at the University of Kansas Medical Center, “this innovative gene therapy approach targets the fundamental calcium handling defects that drive heart muscle deterioration in DMD patients.”
AAV1.SERCA2 is administered via a minimally invasive one-time intracoronary infusion method, in which a catheter is threaded through large vessels in the arm or legs to reach the coronary arteries, the main blood vessels in the heart.
Li noted that this “proprietary intracoronary infusion methodology … has been shown in other indications to safely and reliably deliver the therapeutic gene directly to affected heart tissue.”
MUSIC-DMD study testing one-time gene therapy in 12 patients
MUSIC-DMD is an open-label study designed to evaluate the safety and efficacy of AAV1.SERCA2 in as many as a dozen DMD men with cardiomyopathy. Participants will continue to take their current heart medications and receive either a low or high dose of the gene therapy or no treatment, serving as a control.
Individuals assigned to active treatment with AAV1.SERCA2 will undergo cardiac catheterization and angiography to visualize the arteries, just before the intracoronary infusion, and spend a night in the hospital for observation.
In addition to safety, the study’s goals are to investigate the effects of AAV1.SERCA2 on heart and skeletal muscle function, as well as its impact on quality of life. All participants will undergo MRI scans of the heart before treatment, as well as at one and two years after treatment. Upper limb function and lung function will also be assessed.
After two years, all participants will transition into long-term follow-up, where they will be contacted twice a year for updates on their current medical status.
According to Medera, the first patient was successfully treated using intracoronary infusion via the left radial artery, a major blood vessel in the left arm. The procedure was well tolerated, and the patient was discharged from the hospital following an overnight stay.
“The successful initiation of this trial marks an important step forward in addressing the cardiac complications that ultimately affect nearly all patients with Duchenne muscular dystrophy,” said Mammen, also a professor of cardiovascular medicine at the University of Kansas Medical Center.
Pat Furlong, the founding president and CEO of Parent Project Muscular Dystrophy and an advocate for advancing cardiac care in Duchenne, noted that “cardiac dysfunction affects all patients with” DMD.
“This novel gene therapy modality targeted to the cardiac muscle promises to have important effects on cardiac care in Duchenne by repairing hearts,” Furlong said.
About the Author
