Preclinical testing of the splice modulating oligonucleotide LSP-GR1

DESCRIPTION provided by applicant AMPA glutamate receptors mediate the majority of fast excitatory neurotransmission in the central nervous system Four AMPA receptor subunits exist GluA GluA with functional channels containing various combinations of these four subunits Dysregulation of AMPA receptor expression has been reported in many neurological disorders including amyotrophic lateral sclerosis ALS a devastating and fatal disease for which no good treatment exists AMPA receptors are alternatively spliced with the best characterized splice variants being the flip and flop isoforms AMPA receptors containing flip vs flop cassettes have distinct channel properties GluA flip and flop variants have similar kinetics but the flip isoform shows greater sensitivity to glutamate increasing synaptic gain Expression of flip channels is associated with greater vulnerability to excitotoxicity and hyperexcitability Increases in GluA flip to flop ratio are found in motor neurons MNs of ALS patients and in a mouse model of the disease Splice modulating oligonucleotides SMOs have unique chemistries and distinct advantages over classic antisense oligonucleotides and siRNA and are in clinical trials for treating muscular dystrophy and spinal muscular atrophy We have developed an SMO LSP GR that specifically and potently reduces GluA flip in vivo LSP GR increases longevity and delays disease progression in a mouse model of ALS The goal of our Phase II SBIR is to perform IND enabling preclinical pharmacology toxicology and CMC studies to set the stage for clinical testing of LSP GR in ALS patients GLP pharmacology toxicology studies will be done in rats and cynomologus monkeys to evaluate toxicity and biodistribution Chemistry Manufacturing and Controls CMC studies will be done to evaluate structure stability and impurities of LSP GR These studies should lead to IND enabling data to allow LSP GR to move forward to clinical testing in ALS patients PUBLIC HEALTH RELEVANCE Project Narrative Amyotrophic lateral sclerosis ALS is a devastating and fatal disease with no cure and no effective drugs to improve quality of life and lifespan The goals of this research are to test the safety of a compound LSP GR that has the potential to slow disease progression ALS patients Ultimately the goal of our program is to determine whether LSP GR is a safe and effective drug to treat patients with ALS