Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophyOjala, Kristine (2020) Potentiation of neuromuscular transmission as a therapeutic strategy to improve motor function in spinal muscular atrophy. Doctoral Dissertation, University of Pittsburgh. (Unpublished) This is the latest version of this item.
AbstractSpinal Muscular Atrophy (SMA) is a genetic disease caused by a null mutation of the SMN1 gene. Loss of SMN1 results in low levels of a protein called Survival of Motor Neuron (SMN), which is a protein that is critical for neuromuscular development. The first FDA-approved treatment utilizes intrathecal injections of an antisense oligonucleotide (ASO) to increase expression of SMN. Despite the immense excitement for this treatment, however, preliminary clinical observations and studies in SMA mouse models indicate persistent neuromuscular weakness, which reveals the need for an additional symptomatic treatment that targets neuromuscular function. Thus, supplemental strategies are required to address the neuromuscular deficits that remain after ASO therapy. In our preclinical investigations, we have tested a calcium channel gating modifier (GV-58), which significantly increases transmitter release from weakened motor nerve terminals, in combination with a potassium channel blocker (3,4-diaminopyridine; 3,4-DAP). 3,4-DAP is a drug commonly prescribed to patients with specific motoneuron diseases, but scientists have debated channel selectivity and concentration-response effects. To address these questions, my colleagues and I have characterized the mechanism of action of 3,4-DAP at neuromuscular junctions across two species (Chapter 2). Our results have provided novel insight into the concentration-dependent effects of 3,4-DAP on presynaptic voltage-gated potassium channels, as well as physiological effects on presynaptic action potentials and the magnitude of transmitter released. We next provide proof of principle that 3,4-DAP can be combined with GV-58 to increase strength and improve neuromuscular function in an SMA model mouse (Chapter 3). We have found that GV-58 alone is an excellent therapeutic candidate to restore neuromuscular function and increasing strength in more mild forms of SMA, but severe forms of SMA optimally benefit from GV-58 combined with 3,4-DAP. The preclinical investigations contained within this dissertation provide the initial research necessary to explore the efficaciousness of a novel treatment that complements current approaches by addressing persistent deficits after ASO therapy. Share
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