AAV Platform Vector Gene Therapy (PaVe-GT) for DOK7 Congenital Myasthenic Syndromes


Pre-Clinical Research

Poster Number: 4


Janelle Geist Hauserman PhD, Eric Esposito , Richa Lomash PhD, Elizabeth Ottinger PhD, Julien Oury PhD, Steven Burden PhD, Philip John (PJ) Brooks PhD, Anne Pariser MD, Carsten Bönnemann MD


1. National Institutes of Health, 2. NIH, NINDS, NNDCS, 3. National Institutes of Health, 4. National Institutes of Health, 5. NYU Grossman School of Medicine, 6. NYU Grossman School of Medicine, 7. National Institutes of Health, 8. National Institutes of Health, 9. NINDS/NIH, Bethesda, MD

Congenital myasthenic syndromes (CMS) are a class of rare genetic diseases that affect approximately 1:100,000 children. They are categorized by early onset diminished motor function due to dysfunction of neuromuscular junction (NMJ) proteins. Adeno-associated virus (AAV)-based gene therapy offers an attractive method for treatment of CMS, in particular for loss of function situations that would benefit from gene replacement approaches. AAV based therapies for various neuromuscular disorders are in clinical trials with one for SMA that reached FDA approval. While promising, the development of each therapy requires complex commitments that will be difficult to realize for ultrarare disorders.

CMS as a group are rare, but even more so when individual genetic entities are considered. Therefore, the development of individual gene specific therapies is very challenging. However, all relevant gene products are localized in the same well-defined structure while their dysfunction results in related clinical manifestations of impaired neuromuscular transmission. Thus, when considering a gene replacement approach using AAV as a tool, various CMS could be grouped and addressed with the same AAV serotype, expression/promoter construct, outcome measures and trial design. This idea is the basis for the Platform Vector Gene Therapy (PaVe-GT) project initiated by the National Center for Advancing Translational Science which explores the feasibility of such grouped platform approaches.

One of the most common recessive forms of CMS, DOK7 deficiency, will be addressed initially. DOK7 is a regulator of acetylcholine receptor assembly necessary for postsynaptic NMJ formation. We have begun to study the use of self-complementary AAV and various vector/expression constructs to target the NMJ’s subsynaptic nuclei that will then be used to treat a Dok7 mouse model to determine if gene therapy is successful at restoring NMJ structure and muscle function.