Advancements in Gene Therapy: Treating DMD and SMA at UPMC Children’s Hospital of Pittsburgh

Pediatric neuromuscular conditions, such as Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), have historically posed significant challenges in treatment and management, often leading to progressive disability, decreased quality of life, and far too frequently death for affected children. At UPMC Children's Hospital of Pittsburgh, the Neuromuscular Program and MDA Clinic are designed to address these challenges through comprehensive care and cutting-edge research.

The Neuromuscular Program at UPMC Children’s Hospital of Pittsburgh provides comprehensive, multidisciplinary care for children and families for all neuromuscular disorders. At the same time, the specialized MDA Clinic at UPMC Children’s, supported by the Muscular Dystrophy Association, is focused on treating all forms of muscular dystrophy — most notably Duchenne Muscular Dystrophy (DMD). The clinics provide a multidisciplinary setting for the diagnostic evaluation and follow-up care of infants and children with known or suspected neuromuscular disorders. Combining child neurology, pulmonology, cardiology, physiatry, orthopaedics, genetic counseling, social work, and physical therapy all into one setting streamlines care for patients while working to optimize long-term outcomes through a holistic approach.

Pediatric neurologist Hoda Z. Abdel-Hamid, MD, Professor of Pediatrics at the University of Pittsburgh School of Medicine, leads these clinical programs at UPMC Children’s. Dr. Abdel-Hamid is the director of the EMG Laboratory and the Pediatric Neuromuscular Program, and she also directs the multidisciplinary Muscular Dystrophy Association (MDA) Clinic, PPMD Center of Excellence and CMT Center of Excellence.

In recent years, the development and approval of gene-based therapies have begun to shift the landscape of pediatric neuromuscular treatment approaches. In 2019, the first gene therapy for SMA (Zolgensma^®) was approved by the U.S. Food and Drug Administration (FDA), offering new hope for affected patients. More recently, in June 2023, the first gene therapy for DMD (Elevidys®) received FDA approval for use in targeted cases, opening a new era in treating these debilitating conditions.

UPMC Children’s Begins Using DMD Gene Therapy

Since its approval in mid-2023, UPMC Children’s has treated two individuals with DMD with the new Elevidys gene therapy.

"In June of 2023, the therapy was only approved for use in cases with specific gene mutations, and only in children 4 or 5 years of age, along with other criteria," says Dr. Abdel-Hamid. "But this just changed as of June of 2024 to expand therapy to all patients with DMD over 4 years of age and only excluding certain mutations over time as the evidence accrues from clinical trials and observational data in patients who have received the therapy. Gauging long-term efficacy will take time.”

The Treatment Process

The gene therapy for DMD works by delivering a functional, shortened version of the dystrophin gene, known as a "mini-dystrophin," to muscle cells. This mini-dystrophin gene is carried into the body using an adeno-associated virus (AAV) vector as a delivery vehicle. The AAV vector is administered via intravenous infusion, allowing it to travel through the bloodstream and reach muscle tissue. Once inside the muscle cells, the mini-dystrophin gene produces a functional dystrophin protein essential for muscle integrity and function. This therapy aims to slow the progression of muscle degeneration and improve muscle strength and function in patients with DMD.

“The single-infusion treatment is conducted in the hospital's outpatient center,” says Dr. Abdel Hamid. “We administer a high dose of steroids before the infusion to prepare the body. Post-treatment, our patients undergo regular monitoring to manage any side effects and assess the therapy's efficacy over time, which will be measured in years.”

As Dr. Abdel-Hamid explains, the therapy's long-term effectiveness will be measured by comparing the patients' outcomes to the natural history of the disease and their expected trajectory.

“We are observing and monitoring a patient’s strength, motor function, cardiac function, and other biomarkers against what would typically be expected in the natural progression of DMD,” says Dr. Abdel-Hamid.

Dr. Abdel-Hamid notes that it is important to understand that patient responses to gene therapy can and will likely vary. Some patients may respond more favorably than others, and since the therapy is relatively new, the long-term effects and longevity of the treatment are not yet clear.

"We hope that gene therapy will provide a cure, but at this stage, it’s much too early to know,” says Dr. Abdel-Hamid.  “Currently, it appears to be the closest approximation to a cure, yet several uncertainties remain, such as the longevity of the therapeutic effects and the variability in patient responses. Furthermore, the gene used in the therapy is not identical to the natural gene that is mutated in our patients. The large size of the natural gene presents challenges in incorporating it into a viral vector shell, and there can be immune-related complications associated with the viral vector. Therefore, there is a need for improved vectors and potentially a different construct that more closely resembles the natural gene.”

Gene-based Treatments for SMA

UPMC Children's began offering the gene therapy Zolgensma for the treatment of SMA shortly after it was FDA-approved in 2019. In the intervening five years, Dr. Abdel-Hamid and colleagues have treated 13 patients with the therapy.

SMA is a genetic disorder characterized by the loss of motor neurons in the spinal cord, leading to muscle weakness and atrophy. In infants with SMA Type 1, the most severe form, symptoms typically appear within the first six months of life. Without treatment, these infants often experience significant respiratory and feeding difficulties, leading to a high risk of mortality, usually within the first two years of life.

Zolgensma works by delivering a functional copy via an AAV-vector of the SMN1 gene, which is defective or missing in patients with SMA. Clinical trials and real-world data have shown that Zolgensma can significantly improve motor function and increase survival rates, particularly when administered early in the disease process.

“SMA, particularly in its most severe form, is a fatal disease,” says Dr. Abdel-Hamid. “However, patients in our clinic have been achieving significant milestones with the gene-therapy. Those who would have previously succumbed to the disease by six months to a year of age are now reaching four and five years with almost normal motor development.”

Looking at the Future of Gene Therapy

The recent advancements in gene therapy for DMD and SMA represent significant steps forward in treating these debilitating conditions. While not yet cures, these therapies may offer substantial improvements in patient outcomes and quality of life. Ongoing research and patient monitoring will be essential to fully understand the long-term benefits and limitations of these treatments. With the dedicated efforts of the Neuromuscular Program and MDA Clinic, UPMC Children’s continues to provide innovative and comprehensive care for children affected by neuromuscular conditions.