Congenital myasthenic syndromes (CMS) are a class of rare diseases that affect approximately 1:100,000 children, categorized by early onset diminished motor function due to dysfunction of neuromuscular junction (NMJ) proteins. Two of the most common recessive forms of CMS are deficiencies of DOK7, a regulator of acetylcholine receptor assembly that is necessary for postsynaptic NMJ formation, and of COLQ, the collagen tail subunit of acetylcholinesterase, anchored in the synaptic cleft.
Adeno associated virus (AAV)-based gene therapy offers an attractive method for the treatment of CMS, in particular for loss of function situations, like DOK7 and COLQ deficiencies, that would benefit from gene replacement approaches. These various CMS subtypes could be grouped and addressed with the same AAV serotype, expression/promoter construct, outcome measures and trial design. Conceivably, such grouping could extend to production, toxicology, and regulatory discussion, making the development of gene therapy for such ultrarare genetic disorders more feasible.
This idea is the basis for the Platform Vector Gene Therapy (PaVe-GT) project initiated by the National Center for Advancing Translational Science (NCATS) which explores the feasibility of such grouped platform approaches. Our preliminary approach uses self-complementary AAV vector/expression constructs with various promoters and GFP as the “transgene.” As such, we have begun to test the efficiency of each promoter at targeting sub-synaptic NMJ expression through both biochemical and fluorescence microscopy-based methods.
After determination of the most effective NMJ-targeting construct, we will deliver human codon-optimized COLQ transgene in preclinical Colq knockout mouse model to determine if the gene therapy is successful at restoring NMJ structure and muscle function. We thus plan to demonstrate this platform-based gene therapy approach from conception, preclinical optimization, production, toxicology studies, regulatory filings and interactions, all the way to a clinical trial and make all learning from this fully available.