Background: Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurological disease with unclear etiology, which is characterized by axon degeneration, denervation, and the loss of motor neurons that control voluntary muscle movement. There is an urgent need for the development of novel effective therapies for this devastating disease that preserve both axons and motor neuron cell bodies. In the past 22 years only two drugs have been approved, Rilutek (riluzole) and Radicava (edavarone). They provide only very minor slowing of disease progression, if at all, and their benefit remains controversial.The discovery of neurotrophic factors, which prevent the loss of motor neurons in cellular and animal models of ALS and axon injury, has raised the hopes for effective treatments. Perhaps the most promising candidate was ciliary neurotrophic factor (CNTF), a potent neurotrophic factor in the interleukin-6 (IL-6) family of cytokines that has been shown to prevent not only the loss of motor neurons, but also axonal degeneration. Signaling of human CNTF is mediated primarily via high-affinity-binding to a tripartite receptor complex containing CNTF alpha receptor (CNTFR). In addition, human CNTF can bind and activate an alternative receptor in which CNTFR is substituted by the IL-6 alpha receptor (IL-6R). Despite the promising preclinical data in animal models, subsequent large clinical trials with systemic delivery of recombinant CNTF protein in human ALS patients have been unsuccessful, due to its poor pharmacokinetic profile, patients developing an immune response to CNTF, and adverse side effects via promiscuous binding to IL-6R, which activates a deleterious acute phase response. While small molecule mimics have been developed successfully for brain-derived neurotrophic factor (BDNF) and other neurotrophic factors, the most promising agonist for CNTFR is a mutated version of the protein with increased selectivity for CNTFR, but unresolved problems of short half-life and immunogenicity remain.Hypothesis and Objective: It is our central hypothesis that we can identify selective small molecule agonists of CNTFR that have the potential to solve these problems, which caused the failure of clinical trials with CNTF protein. Our objective is to address the need for potent and selective small molecule CNTFR agonists for systemic treatment of patients with ALS.Study Design and Specific Aims: Here we propose a collaboration to develop a cell-based high throughput screen (HTS) and follow-on biological assays to discover and validate small molecules that protect motor neuron function and survival by specifically activating CNTFR but not IL-6R complexes. Our specific aims are to (1) establish assays based on ALS patient-derived induced pluripotent stem cells differentiated into motor neurons (iPSC-MNs) for selective CNTFR agonists, (2) conduct an HTS of a large and diverse chemical library to identify selective CNTFR agonists, confirm and validate hits through secondary and tertiary assays, and (3) characterize promising therapeutic agents from the HTS screen.Innovation: These studies are likely to identify novel small molecules with great potential for future development into therapeutics for ALS and other neurodegenerative disorders. It is thus highly relevant to active duty Service members, Veterans, military beneficiaries, and the American public. The innovation for this phase lies in its target selection (=non-peptide small molecule agonist of CNTFR) and unique screening method specifically designed to address side effects in previous human trials (=high specificity against IL-6R activation): (1) This is the first attempt to discover non-peptide small molecule agonists of the CNTF receptor (CNTFR) complex. (2) Unlike other drugs aimed at motor neuron survival, CNTFR agonists also target the underlying biology of axon and neuromuscular junction (NMJ) maintenance. (3) This proposal is exploiting unique features of an engineered cell line to identify compounds with high selectivity against the key counter-target IL-6R, thus eliminating off-target effects.Impact: ALS is a fatal neurodegenerative disorder that is twice as likely to affect military Veterans, but currently there is no cure or effective treatment to halt or reverse the progression of this. The proposed project will impact the development of therapeutics for ALS by using a novel approach -- the development of small molecule agonists -- to target the CNTF signaling pathway as a highly promising and well-researched target for ALS therapy. This proposal is thus highly relevant to active duty Service Members, Veterans, military beneficiaries, and the American public.
|Effective start/end date||7/15/19 → 7/14/21|
- Congressionally Directed Medical Research Programs: $598,875.00