The professor at the University of Pittsburgh was awarded a $190,000 grant for mouse model research that specifically targets neuromuscular weakness in spinal muscular atrophy.
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Cure SMA has awarded a $190,000 research grant to Stephen Meriney, Ph.D., at the University of Pittsburgh for his project titled, “A novel treatment targeting persistent neuromuscular dysfunction in a mild mouse model of SMA.”
Dr. Meriney and his team note that, currently, the only approved therapies for SMA work by increasing SMN protein levels. However, it is unlikely that elevated SMN levels will sufficiently reverse established neuromuscular defects in patients treated after symptom have started.
These defects contribute to neuromuscular weakness and are likely to increase neuromuscular susceptibility to premature aging-related decline.
Dr. Meriney proposes an SMN-independent strategy that specifically targets neuromuscular weakness and can also be combined with SMN-based therapeutics. Using a mild SMA mouse model, he will evaluate the effectiveness of chronic treatment with a novel small molecule (called GV-58) in the presence and absence of a known potassium channel blocker (3,4-diaminopyridine, DAP). GV-58 works by holding voltage-gated calcium channels open longer than normal, increasing calcium ion entry and subsequently increasing neurotransmitter release from motor nerve terminals, where the motor neuron connects to the muscle. This increase in neurotransmitter release allows for increased muscle contraction. GV-58 and DAP have been shown to have synergistic effects when co-administered, causing an increase in neurotransmitter release that greatly exceeds the effect of either drug alone.
Dr. Meriney: I received my Ph.D. training at the University of Connecticut, focused on physiology and neuroscience, and then completed a postdoctoral fellowship under the guidance of Dr. Grinnell at University of California, Los Angeles in the neuromuscular research center. After this training in neuromuscular research, in 1993, I was recruited to the Department of Neuroscience at the University of Pittsburgh, where I started a research program focused on motor nerve terminals, ion channels, and neuromuscular diseases.
I was introduced to SMA research after a conversation with Dr. Chien-Ping Ko, who encouraged me to lend my expertise to this disease. This led me to acquire mouse models of SMA and begin exploring potential contributions to this field.
My lab uses SMA model mice to characterize disease-induced changes in the neuromuscular synapse, explore alterations in behavior and muscle strength, and develop and test of a novel symptomatic treatment approach. Our novel treatment approach is designed to be used in combination with existing therapies for SMA.
The objective of the proposed work is to test the effectiveness of a novel treatment strategy designed to combat muscle weakness for mild forms of SMA in model mice.
The strategy is to use a mild SMA mouse model to test a novel small molecule that increases calcium influx into motor nerve terminals. This small molecule (GV-58) holds voltage-gated calcium channels open longer than normal and can significantly increase neurotransmitter release from motor nerve terminals, allowing for increased muscle contraction.
Patients with mild forms of SMA would benefit greatly from a treatment that targets muscle weakness at the neuromuscular synapse directly. The proposed project would test a novel molecule that might strengthen the neuromuscular synapse in mild SMA.
This grant to Dr. Meriney is part of $1,100,000 in new basic research funding that we’re currently announcing. Basic research is the first step in our comprehensive research model. We fund basic research to investigate the biology and cause of SMA, in order to identify the most effective strategies for drug discovery. We also use this funding to develop tools that facilitate SMA research.