Amyotrophic lateral sclerosis (ALS) is a progressive, disabling and ultimately fatal neuromuscular disease which has increased incidence in veterans and upon which currently available therapies have only nominal effects. The overall goal of this proposal is to determine whether a small molecule modulator of the p75 neurotrophin receptor (p75NTR) will inhibit progression of pathology and improve outcomes in ALS. Impaired neurotrophin-mediated signaling and activation of p75NTR-associated death mechanisms have been implicated as potential drivers of ALS pathology. Moreover, p75NTR is upregulated in motor neurons at risk for injury and death in ALS, and shedding of the extracellular domain of the receptor, a reflection of ligand engagement and signaling, correlates with disease progression. Prior studies employing peptide ligands and receptor down-regulation to therapeutically target p75NTR have yielded mixed results, perhaps in part due peptide instability, inadequate dosing, lack of target engagement, and/or interference with positive aspects of p75NTR activity. Non-peptide small molecule orally-bioavailable p75NTR ligands have been developed that can inhibit injurious signaling and promote survival pathways via the receptor. They have been found to have positive effects on signaling, pathology and behavioral outcomes in several neurodegenerative and injury paradigms, including ALS cell culture models. We hypothesize that LM11A-31, a p75NTR ligand currently in phase II testing for Alzheimer?s disease, will inhibit the initiation and/or progression of ALS-associated cell death signaling, pathology, symptoms and mortality. We will determine LM11A-31 effects on the course of functional status, weight and survival in animals carrying the ALS-inducing SOD1G93A mutation, and examine: LM11A-31 pharmacokinetics; effects on p75NTR proteolytic processing, urinary excretion and binding to its native ligands; and, activation of death and survival-related signaling pathways. In addition to classical apoptotic pathways, we will examine effects on necroptotic death pathways which may be associated with the disease. A second ALS mouse model, bearing the FUSR521C mutation and known to have deficits in neurotrophic signaling, will be examined for p75NTR expression patterns as well as effects of LM11A-31 on signaling. We expect that treatment with LM11A-31 will delay onset and/or progression of symptoms and death in the SOD1G93A mice, and will normalize much of the associated deleterious signaling in those and FUS R521C mice. Positive results of these studies would support p75NTR as a therapeutic target in ALS, and would facilitate testing of LM11A-31 in ALS patients. Further, these results could add to knowledge of the role of p75NTR in ALS and its relationship to non-apoptotic death mechanisms.
Amyotrophic lateral sclerosis, ALS, is a devastating neurologic condition which relentlessly progresses to se- vere weakness and death. Current therapies have limited effectiveness, and new treatments are needed. This proposal, to test a promising nerve cell-survival-promoting compound (called LM11A-31), which is already in human testing for Alzheimer?s disease, in models of ALS, addresses this need directly. The proposed experi- ments will determine whether treatment with LM11A-31 will improve symptoms and survival in mice genetically engineered to develop ALS. In addition, they will provide insight into questions regarding the mechanisms by which the compound affects cell survival and inflammation. If effective, treatment with LM11A-31 or other com- pounds of this type could represent an important advance in the development of new therapies for ALS.
