Phase 1/2 study of Nationwide GALGT2 Gene Therapy in people with Duchenne

Viral gene transfer for GALGT2 (rAAVrh74.MCK.GALGT2) as a surrogate gene therapy

Questions and Answers

What stage is this research?

This Phase 1/2 trial is enrolling participants by invitation only.

What is the goal or purpose of this study?

The goal of this study is to introduce the GALGT2 gene into the body by using a viral vector (an adeno-associated virus, or AAV). Because the virus carries GALGT2 rather than a version of the dystrophin gene, it is a “surrogate” gene therapy.

GALGT2 encodes the protein GalNAc transferase (beta 1,4 –N-acetylgalactosamine galactosyltransferase). This is an enzyme that transfers a complex sugar molecule onto a few specific proteins, including dystroglycan.

Usually, GalNAc transferase is found only at the neuromuscular junction (NMJ), where some components of the dystroglycan-associated protein complex are different than elsewhere in muscle. Importantly, at the NMJ, utrophin is present instead of dystrophin.

In the mdx mouse, viral gene transfer of GALGT2 results in expression of GalNAc transferase across the entire muscle membrane (instead of just at the NMJ), as well as upregulation of utrophin across the entire muscle fiber.

In the mdx mouse, this expression can correct muscle functional deficits to the same degree as does microdystrophin gene expression. Furthermore, overexpression of GALGT2 corrects muscle pathology in mouse models of other muscular dystrophies, including LGMD2A and congenital muscular dystrophy (MDC1A).

This AAV viral vector is known not to cause disease. The vector includes a gene promoter that is specifically activated in muscle tissue, so the gene should not be significantly activated in other tissues. The AAV-delivered gene is not integrated into chromosomal DNA.

Because the GalNAc transferase is already expressed in patients, there should not be any immune response generated to the transferred gene’s protein product.

Who is funding this study?

Development, preclinical testing, and the clinical trial have been funded by the NIH.

Who is eligible to participate in this study?

Participants must be ambulant boys with Duchenne, age 4 years or older.

What do I have to do if I decide to participate in this study?

This is a dose escalation trial where participants will receive a modified intravascular limb infusion (ILI) procedure that will be used to sequentially deliver viral vector to each lower limb via a major lower limb artery. Safety endpoints will be assessed by changes in hematology, serum chemistry, urinalysis, immunologic response to rAAVrh74 and GALGT2. Efficacy measures will be used as secondary outcomes including a combination of functional 6 minute walk test (6MWT) and direct muscle testing for strength (MVICT) of lower limb muscles.

Where does this study take place?

The clinical trial will take place at Nationwide Children’s Hospital (NCH) in Columbus, Ohio, and will include multiple visits to this site.

How long will this study last, and will I have access to the drug/treatment once the study has ended?

The study will require follow up for two years after injection.

Patients who participate in this study are unlikely to be eligible for follow up vascular delivery studies, due to the expected development of antibodies to the viral capsid.

If the treatment were to be approved by the FDA, plasmapheresis to clear anti-AAV antibodies may allow future treatment, although this cannot be guaranteed at present.

Why should I consider participating in this study?

Although there is no guarantee of personal benefit by participating in this clinical trial, there may be other benefits. These include allowing you or your child to participate in the advancement of a new and promising therapy, and helping others by contributing to the better understanding of Duchenne.

Where can I learn more about this study?

You will be able to learn more about this study at ClinicalTrials.gov (NCT03333590).

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