DM1 gene therapy trial seeks patients ages 10-50
Sanofi-sponsored study recruiting at sites in Florida, New York, Argentina
A Phase 1/2 clinical trial testing SAR446268, an experimental gene therapy for myotonic dystrophy type 1 (DM1), is enrolling patients.
The trial, dubbed BrAAVe (NCT06844214), is expected to enroll approximately 32 DM1 patients aged 10-50. The study is actively recruiting participants at sites in Florida, New York, and Argentina. It’s sponsored by Sanofi, the company developing SAR446268.
In the study’s first part, participants will be given a single infusion of SAR446268 at one of several doses, with the main goal of evaluating safety. Based on findings from the first part, a dose will be selected for the second part, which will further evaluate safety and look for proof that the therapy seems to be working as intended.
DM1 is caused by mutations in the DMPK gene that lead to the production of an abnormally long messenger RNA (mRNA), an intermediary molecule produced when genes are read to make proteins. The abnormally long DMPK mRNA forms clumps in muscle cells, causing damage that ultimately drives disease symptoms.
SAR446268 is designed to reduce levels of DMPK mRNA in muscle cells. The development and preclinical testing of the therapy were described in the study, “Development of an AAV-delivered microRNA gene therapy for Myotonic Dystrophy Type 1,” published in Molecular Therapy. The work was funded by Sanofi.
Treatment shows promise in animal studies
To create SAR446268, researchers combined three key elements. The first was a microRNA, a small RNA molecule designed to bind to the DMPK mRNA and degrade it. The second was a muscle-specific promoter, a sequence of genetic code that can ensure the microRNA is activated in muscle cells. The third and final element was a viral vector specifically engineered to deliver the microRNA and promoter into muscle cells.
The viral vector used in SAR446268 contains a modified version of adeno-associated virus (AAV) engineered to deliver a therapeutic gene instead of causing infection. AAV is commonly used as a platform for gene therapy because it’s easy to work with in a lab and doesn’t usually cause serious illness in people.
“Sustained, steady-state, muscle-targeted DMPK suppression facilitated by AAV therapy promises long-term benefits from a single injection,” the researchers noted.
The researchers said the AAV vector used in SAR446268 can deliver genetic material not only to skeletal muscles used for movement, but also to cardiac muscles in the heart, which is noteworthy since heart problems are a leading cause of death in people with DM1.
After creating the gene therapy and running tests in cell models, the researchers tested the treatment in animals. In a mouse model of DM1, SAR446268 significantly reduced myotonia (a hallmark of DM1 where muscles are unable to relax after contracting) in several muscles, and improved the flow of blood out of the heart. Further tests in nonhuman primates showed that the gene therapy was generally well tolerated and reduced DMPK mRNA levels by up to 90% in skeletal and cardiac muscle tissues.
The preclinical data laid the groundwork for the Phase 1/2 BrAAVe study to test SAR446268 in DM1 patients. The study launched in July and is expected to run through 2030.
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