3-drug cocktail boosts DMD gene therapy effectiveness in mice
Regimen could allow re-dosing, treatment of patients not currently eligible
A regimen of three immune-suppressing medications may improve the effectiveness of gene therapy for people with Duchenne muscular dystrophy (DMD), allowing patients to receive treatment more than once and making it accessible to people who are currently ineligible, a mouse study showed.
DMD is caused by mutations in the gene that encodes dystrophin, a protein important for muscle health. Gene therapy for DMD aims to deliver a healthy dystrophin-encoding gene to muscle cells, allowing muscles to produce a functional dystrophin protein and ultimately slowing disease progression.
The only approved DMD gene therapy in the U.S. is Elevidys (delandistrogene moxeparvovec-rokl), which is currently available for certain patients ages 4 and older. Elevidys delivers its payload using an adeno-associated virus (AAV) vector, which is essentially a virus that’s been engineered to deliver a therapeutic gene instead of causing infection.
AAV is commonly used as a platform for gene therapy vectors because it is easy to work with in a lab and typically doesn’t cause illness in people. Using viruses such as AAV for gene therapy has some notable advantages: Viruses have evolved over millions of years to be very, very good at getting new genes into cells.
But there are also drawbacks. The immune system cannot distinguish between a viral vector used in gene therapy and an infectious virus, so it responds to both in the same way, producing antibodies to neutralize the perceived threat. This means that AAV-based gene therapies can usually be given only once. After the first dose, patients will have antibodies against the viral vector that will stop the treatment from working. And since AAV exists naturally in the world, some DMD patients have preexisting antibodies against the virus, so they can’t receive the therapy.
Testing immune response
A team of scientists in the U.S. wanted to see if they could use immune-suppressing medications to minimize immune responses against an AAV vector used in gene therapy. In theory, this could enable gene therapy to be administered more than once, potentially making the treatment more effective and allowing some patients who are currently ineligible to benefit from it.
The study, “Enhancing AAV9-UF[mu]Dys1 Gene Therapy Efficacy Through Immunosuppression in Mice with Preexisting Immunity and Enabling Redosing Strategies for Duchenne Muscular Dystrophy,” was published in Human Gene Therapy.Â
The researchers conducted a series of tests in a mouse model of DMD using an investigational gene therapy called AAV9-UFmcDys1. Like Elevidys, the treatment uses an AAV vector to deliver a gene encoding a shortened yet functional version of the dystrophin protein to muscle cells.
The scientists first injected mice with an empty AAV vector to trigger the production of antibodies against the vector. They then gave the mice various regimens of immune-suppressing therapies, to subsequently treat them with the active gene therapy.
Through these experiments, the researchers zeroed in on a combination of three medications: rituximab, sirolimus, and bortezomib. Rituximab, used to treat certain types of blood cancer and autoimmune diseases, works by targeting and killing B-cells, the immune cells responsible for producing antibodies. Bortezomib is also used to treat certain blood cancers and is believed to reduce the activity of antibody-producing immune cells. Sirolimus, used to prevent organ transplant rejection, is a potent immunosuppressant that inhibits immune cell activation and growth.
When mice with preexisting AAV antibodies were given this three-drug regimen before gene therapy, levels of the microdystrophin protein were more than 20 times higher than in mice that didn’t receive immune-modulating treatment. The researchers also demonstrated that this treatment combination reduced levels of anti-AAV antibodies as designed.
This three-medication approach “demonstrates relative safety and potential for wide-ranging gene therapy applications,” the researchers wrote. They stressed, however, that further work will be needed and that the use of bortezomib can sometimes cause serious side effects.
“Although this approach may be promising for DMD treatment in patients with preexisting anti-AAV antibodies, potential clinical considerations would weigh the risk and benefits, including prolonged suppression of immune response, costs, and adverse effects,” the team concluded.
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