Triple-Drug Strategy May Unlock Repeat Dosing and Expand Eligibility for DMD AAV Gene Therapy

December 04, 2025- A significant barrier in AAV (adeno-associated virus) gene therapy for Duchenne muscular dystrophy (DMD) could be overcome using a combination of three immune-suppressing medications, according to a recent mouse study. This regimen successfully suppressed the immune response against the AAV vector, potentially allowing patients to receive AAV gene therapy more than once and making it accessible to those currently ineligible due to preexisting anti-AAV antibodies.

The research, titled “Enhancing AAV9-UFµDys1 Gene Therapy Efficacy Through Immunosuppression in Mice with Preexisting Immunity and Enabling Redosing Strategies for Duchenne Muscular Dystrophy,” was published in Human Gene Therapy.

The Challenge of AAV Immunity

DMD gene therapy, such as the U.S.-approved Elevidys, relies on the AAV vector to deliver a functional microdystrophin gene to muscle cells. While the AAV platform is highly efficient at gene delivery, the immune system recognizes the AAV as a foreign invader.

• The Barrier: The immune response produces antibodies against the AAV capsid. Once this immune memory is established, a second dose of the AAV gene therapy is rendered ineffective. Additionally, many DMD patients naturally possess preexisting anti-AAV antibodies, automatically excluding them from receiving the single-dose AAV therapy.

Immunosuppression Targets Anti-AAV Antibodies

Scientists sought to minimize the immune response against the AAV vector using a regimen of immune-suppressing medications. They tested the approach using the investigational AAV9-UFµDys1 gene therapy in a DMD mouse model.

The optimal immunosuppression (IMS) regimen identified combined three clinically used drugs, each targeting a different part of the antibody production process:

1. Rituximab: A monoclonal antibody that targets and kills B-cells, which are responsible for producing antibodies.

2. Bortezomib: Reduces the activity of plasma cells, the long-lived immune cells that maintain antibody production.

3. Sirolimus: A potent immunosuppressant that inhibits the activation and growth of immune cells.

Restoring Eligibility

In mice that were first injected with an empty AAV vector to simulate preexisting anti-AAV antibodies, the subsequent three-drug IMS regimen proved highly effective.

• Mice receiving the IMS regimen before the AAV9-UFµDys1 gene therapy showed microdystrophin protein levels more than 20 times higher than mice that went untreated.

• This treatment also successfully reduced the levels of anti-AAV antibodies, confirming the potential of this AAV-based strategy to allow currently ineligible patients to benefit from AAV gene therapy.

The researchers believe this IMS approach, which “demonstrates relative safety and potential for wide-ranging gene therapy applications,” may be the key to enabling repeat administration of AAV vectors. The ability to safely redose the AAV vector could be crucial for maintaining therapeutic protein levels and ensuring the long-term efficacy of DMD treatment.

However, the team cautioned that clinical translation must carefully consider the potential risks and adverse effects associated with prolonged immune suppression before implementing the regimen in human AAV gene therapy trials.