Tragic Updates from Sarepta’s Gene Therapy Programs

In July 2025, the rare disease community was shaken by the news that Sarepta Therapeutics had confirmed a third patient death linked to its experimental AAV-based gene therapies. This most recent loss involved an adult participant enrolled in a clinical trial for limb-girdle muscular dystrophy (LGMD), identified as the SRP‑9004 trial. The patient, a 51-year-old man, died due to acute liver failure, a known but serious risk in some gene therapy studies.

Sadly, this is not an isolated incident. Earlier this year, in March and June, two teenage boys living with Duchenne muscular dystrophy (DMD) also died after receiving Elevidys, Sarepta’s approved gene therapy for DMD. Both cases were also tied to sudden, severe liver failure—despite Elevidys being seen as a promising treatment designed to help slow muscle degeneration by delivering a shortened version of the dystrophin gene. While gene therapy remains one of the most promising frontiers for conditions like DMD and LGMD, these recent events highlight the delicate balance between pioneering treatments and patient safety.

As the FDA, Sarepta, and independent safety panels examine what went wrong, families are left with difficult questions: What are the risks? How transparent is the process? Should treatments continue for those already receiving them? And most importantly—how do we keep hope alive while demanding better safeguards?

What Happened: A Timeline of Events

Understanding the sequence of these events can help families and advocates grasp how quickly concerns unfolded in Sarepta’s gene therapy programs:

March 2025: First Reported Death

A 16-year-old boy with Duchenne Muscular Dystrophy (DMD) who received Elevidys died from acute liver failure. Reports indicated that the patient had a concurrent cytomegalovirus (CMV) infection, which may have worsened liver stress during the immune response triggered by the gene therapy. This incident raised initial concerns, but the cause was considered multifactorial.

June 2025: Second Death in DMD Trial

A second non-ambulatory teenage boy with DMD also died from acute liver failure after receiving Elevidys. This prompted Sarepta to pause Elevidys dosing in non-ambulatory DMD patients while investigating safety measures, including adjustments in immunosuppression protocols to mitigate liver complications.

July 2025: Third Death in LGMD Trial

In July, Sarepta confirmed the death of a 51-year-old man with Limb-Girdle Muscular Dystrophy (LGMD) participating in the SRP‑9004 gene therapy trial, also due to acute liver failure. This trial uses a similar AAVrh74 vector platform as Elevidys, raising concerns about potential risks across Sarepta’s AAV-based gene therapy pipeline.

Why AAV Gene Therapy Carries Liver Risks

AAV-based gene therapies, like Elevidys and Sarepta’s LGMD programs, use adeno-associated virus (AAV) vectors to deliver new genetic material into the body’s cells. These viral vectors are designed to be safe and are commonly used because they do not cause disease in humans. However, they can still trigger immune system reactions and liver stress, leading to potential complications.

How It Works

When AAV gene therapy is infused into the bloodstream, it travels to the cells—often targeting muscle tissue in conditions like Duchenne or LGMD—to deliver a working copy of a gene (such as micro-dystrophin). Before reaching muscle cells, a large portion of the therapy passes through the liver, which acts as the body’s filter.

Why the Liver Is at Risk

Because the liver processes a high dose of the viral vector, it can trigger immune activation and inflammation in the liver. In most cases, this can be managed with immune-suppressing medications like corticosteroids, but in rare situations, the immune response can become severe, leading to acute liver injury or even liver failure.

The risk may increase in:

• Patients with pre-existing liver conditions (including undiagnosed issues).

• High-dose gene therapy administration.

• Concurrent infections (like CMV) that strain the liver further.

• Patients who are older or non-ambulatory as they may process the therapy differently.

FDA Response & Sarepta’s Position

In July 2025, the FDA placed a clinical hold on all of Sarepta’s gene therapy trials for Limb-Girdle Muscular Dystrophy (LGMD) following the tragic death of an adult participant in the SRP‑9004 trial, along with two earlier deaths in Duchenne Muscular Dystrophy (DMD) patients treated with Elevidys. The FDA also requested Sarepta suspend shipments of Elevidys nationwide, signalling serious concerns about the therapy’s safety profile.

Initially, Sarepta declined to pause Elevidys shipments, explaining that the data from ambulatory DMD patients showed no new safety signals and emphasizing differences between the Duchenne and LGMD programs. However, after facing mounting pressure from regulators, the medical community, and advocacy groups—and amid a sharp drop in its stock price—Sarepta agreed to pause shipments while working with the FDA to enhance safety monitoring and update product labelling.

In response to these safety concerns, Sarepta announced it would add a black-box warning for acute liver failure to Elevidys, the highest level of safety alert required by the FDA. Additionally, Sarepta established an independent expert advisory panel, including neuromuscular specialists, hepatologists, and immunologists, to review the deaths and recommend ways to improve patient safety. This panel will evaluate the potential use of enhanced immunosuppression protocols, including medications like sirolimus, to reduce liver complications in patients, particularly those who are non-ambulatory and may be at higher

risk.

What Families Can Do Now

Hearing about safety concerns and patient deaths in gene therapy trials can feel overwhelming, especially when you have been hoping for new treatments for Duchenne or LGMD. It is natural to feel worried, but there are practical steps you can take to stay informed and prepared while the field works through these challenges.

Talk to Your Care Team

If your child or loved one is currently receiving or considering gene therapy like Elevidys, schedule a conversation with your neuromuscular specialist. Ask about:

• How might these recent developments affect your treatment plan?

• Your child’s current liver health and monitoring plans.

• Any additional safety measures your care team is taking during and after treatment?

• Alternative treatment options if gene therapy is paused or delayed.

Your care team can help you weigh the potential benefits and risks based on your loved one’s specific situation.

Monitor for Symptoms

If your loved one has already received gene therapy, watch for any signs of liver stress, including:

• Unusual fatigue

• Yellowing of the skin or eyes (jaundice)

• Dark urine

• Nausea or vomiting

• Abdominal pain

Contact your care team immediately if these symptoms appear.

Connect with the Community

You are not alone. These developments affect many families in the rare disease community. Connecting with other caregivers and advocacy organizations can help you share concerns, learn about how others are navigating these changes, and access emotional support during uncertain times.

Maintain Hope While Advocating for Safety

Gene therapy still represents hope for slowing disease progression in rare neuromuscular conditions. The current clinical holds and additional safety reviews, while difficult, are steps to ensure that when treatments are available, they are as safe and effective as possible for patients.

Looking Ahead with Caution and Hope

The recent deaths in Sarepta’s gene therapy trials are a heartbreaking reminder of the complexities and risks that can accompany groundbreaking treatments for rare diseases. For families who have waited years for a chance at slowing disease progression, these developments can feel like a heavy setback, stirring fear, disappointment, and uncertainty.

Yet it is also important to remember that these pauses, reviews, and safety warnings are not signs that hope is lost. Instead, they reflect the careful work of scientists, regulators, and advocates to ensure that treatments are not only effective but as safe as possible for those who need them most. Every step taken now to understand risks, improve monitoring, and enhance treatment protocols helps build a stronger foundation for the future of gene therapy in rare diseases.

Research in gene therapy is still moving forward, with many dedicated teams working tirelessly to find safer and more effective solutions. Families, caregivers, and patient advocates play a critical role in this journey, pushing for transparency, safety, and continued innovation. While the path may feel uncertain today, the collective commitment of the rare disease community, researchers, and regulators keeps the goal of accessible, life-improving treatments alive.

Hope remains—not as blind optimism, but as a commitment to keep pushing forward together until treatments can transform lives safely and sustainably for every individual living with Duchenne, LGMD, and other rare neuromuscular conditions.