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Novel Cell-Based Therapy to Treat Muscle Atrophy Associated with Peripheral Nerve Injury
During this performance period, we found no difference between control and cell therapy arms in mitigation of muscle atrophy in the Lewis rat surgical model (gastrocnemius muscle whose innervation, the sciatic nerve, was severed). After extensive literature review, we identified acetylcholine modulation as a therapeutic target for mitigation of muscle atrophy, with early promising studies using atropine as the therapeutic dating to the 1940s. We confirmed and further demonstrated that local modulation of acetylcholine (ACh) is a promising therapeutic target for mitigation of muscle atrophy caused by damage to the innervating nerves. Nerve damage degrades and/or interrupts signaling between the CNS and muscle, de-modulating ACh release at muscle ACh receptors and in the neuromuscular junction (NMJ), which causes the classic spastic contractile muscle activity that results in muscle atrophy. We showed, in the Lewis rat surgical model, that intramuscular injection of atropine(which reduces ACh receptor activity), essentially eliminated atrophy in a 7-day study, confirming our hypothesis, regardless of the co-injection of cell therapy. Thus we decided to discontinue our cell therapy approach and focus solely on ACh modulation. Since the toxicity profile of atropine is too severe for practical use in this application, we selected an alternative mechanism of reducing local ACh activity, namely, direct binding and removal of ACh via small-molecule ACh chelators. A previous ex-vivo study by one of our collaborators in chick muscle, which demonstrated that ACh chelation modulates muscle contraction, supports this approach.
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