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Screening Therapeutic Agents Targeting Neuromuscular Junctions in ALS

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Ludwig Institute for Cancer Research La Jolla United States

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One of the earliest events in ALS is the loss of the connections between motor neurons and muscles, which are critical for our most basic motor functions such as breathing. The disruption of this connection leads to the destruction of sophisticated structures called neuromuscular junctions NMJs, the contacts that transfer the motor neuron commands onto the muscles. Importantly, the preservation of the motor neurons is not sufficient to prevent the loss of the NMJs, thus pointing to NMJs as potential sites of toxicity. Therefore, targeting NMJs represents an unexplored therapeutic strategy to treat ALS. This project represents a synergistic collaboration between two academic investigators proposing an innovative strategy which combines structural and functional analyses of NMJs in multiple mouse and human in vitro and in vivo models for muscle denervation induced by ALS-causing mutations SOD1, TDP-43 and C9orf72. We proposed to identify small molecules that prevent the disconnection or stimulate reconnection between motor neurons and muscles in ALS. We have assembled a comprehensive set of approaches that will allow us to screen a large number of drugs to identify those that can help maintain NMJs structure and functions. The power of our approach is to then use models that recapitulate the disease at NMJs to more stringently select the most efficient drugs. These models include genetic mouse and human models, including ones from sporadic forms of ALS. This approach, if successful, may identify one or more drugs with the potential to be repurposed for the treatment of ALS. The system can also be used more broadly for identifying completely new drugs that can encourage maintenance of nerve attachment to muscle or stimulate its reattachment.

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Technical Report,15 Jun 2019,14 Jun 2020



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Approved For Public Release;

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