Development of Novel Neuronal Autophagy Inducers to Block Neurodegeneration and Treat ALS
Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive disorder characterized by weakness, muscle atrophy, respiratory failure, and degeneration of motor neurons (MN). No treatment blocks disease progression. Several proteins seem to contribute to ALS. Specifically, mutations in the genes for superoxide dismutase (SOD1), TAR DNA-binding protein (TDP43), fused in sarcoma (FUS), and C9ORF72 cause familial forms of ALS. Furthermore, the normal or wild-type (WT) forms of these proteins might cause neurodegeneration and contribute to sporadic ALS. Much effort has been made to develop drugs to block the toxic actions of SOD1 as potential treatments of ALS. Drug candidates have blocked SOD1 toxicity in animal models expressing mutant forms of SOD1 that cause familial ALS. However, these candidates failed to treat ALS in human clinical trials. One reason for this high failure rate is that only a small portion of ALS cases are caused by SOD1, and drugs designed to block SOD1 toxicity may fail to block the pathophysiology caused by TDP43 and FUS. Type of ALS Patient Helped by Our Therapeutic: We want to find drugs that block the toxic actions of all proteins, including SOD1, TDP43, and FUS, which cause ALS. Thus, we hope to find drugs that will treat most, if not all, ALS patients. Our novel approach focuses on drugs that activate a natural cellular protective mechanism, autophagy. Autophagy is a major pathway for degrading misfolded proteins. It appears to be the only known safe pathway by which cells can clear the aggregated proteins that cause ALS. We propose that this normal defense mechanism is impaired in MNs of ALS patients, and the drugs we will develop will reverse this defect to block disease progression. To develop neuronal autophagy inducers (NAI), we used a novel automated imaging and longitudinal analysis system, called robotic microscopy (RM), to establish cause-and-effect relationships between molecular events in individual neurons and neuronal function. RM enabled us to identify drugs that increase autophagy in primary murine neurons in culture and in human MNs (i-MN) derived from induced pluripotent stem cells (iPSCs) from healthy volunteers and patients with both familial and sporadic forms of ALS. Studying human MNs is a novel aspect of our approach because these are the neurons that are affected most in ALS. Recently, we were the first to show a disease phenotype for ALS i-MNs, and these neurons provide us with robust, definable physiological endpoints to test our new drugs for efficacy. In fact, several of our novel NAIs remove ALS-causing proteins from human i-MNs and reverse the disease phenotype of ALS i-MNs. At doses that protect ALS i-MNs, they do not affect i-MNs from a healthy volunteer, supporting the safety of the compounds and suggesting that NAIs may primarily affect neurons degenerating from the actions of ALS-causing proteins. These results are the first to show small-molecule drugs can reverse the disease phenotype in human ALS MNs and support the feasibility of our approach. Potential Clinical Applications, Benefits, and Risk: Using our innovative drug discovery platform, we identified a series of drugs that increase autophagy in neurons. All of these drugs are Food and Drug Administration (FDA)-approved for treating medical conditions other than ALS. In this study, we will develop a series of Ca2+ channel antagonists in preclinical studies to establish their efficacy in reversing the disease phenotype of ALS i-MNs, stimulating autophagy in the central nervous system in vivo, and blocking disease symptoms in two ALS animal models. If effective in these preclinical studies, these drugs could be tested in ALS patients. After use in millions of patients, they are generally well tolerated and safe. The risk of testing them in ALS patients is minimal, and these agents could prove to be disease-modifying and block the basic mechanisms that cause degeneration on MNs in ALS pat
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Apr 04, 2016
- Source ID
- W81XWH1510158
Entities
People
- Steven Finkbeiner
Organizations
- The J. David Gladstone Institutes
- United States Army