Biomarker Identification by Conjoint Analysis of Metabolites and Gut Microbiome in ALS Patients and Animal Models to Monitor Disease Stages of ALS
Abstract
This grant proposes to develop a disease-modifying treatment of Amyotrophic Lateral Sclerosis (ALS), targeting mitochondrial dysfunction as well as to identify biomarkers that can be used to screen potential ALS patients, differentiate already diagnosed ALS patients into subgroups, and, finally, to assess the therapeutic efficacy of drugs. By combining the 2N Pharma (2N) team s expertise in neurodegenerative disease research and the expertise of our co-applicant, Dr. Barmada, in the research area of ALS/FTD (frontotemporal dementia) with our innovative conceptualization of a new mechanism to treat ALS as a systemic disease rather than focusing on a single symptom, we believe that 2N can bring a novel treatment and a novel biomarker concept into a clinical market that is sorely lacking. The hypothesis behind 2N Pharma s research is based on the connection between metabolic dysfunction and neurodegenerative disease, as we postulate that mitochondrial metabolic imbalance, caused by upregulated enzyme activity that results in aberrant lipid metabolism and deficient glucose metabolism, is a key underlying disease driver of ALS. Pharmaceutical downregulation of enzyme activity inhibits fatty acid oxidation and restores energy homeostasis. Therefore, the objective of this project is to investigate the enzyme inhibition by Mitometin in both in vitro (human neurons derived from ALS patients) and in vivo (mice animal models) studies by assessing the impact of targeting lipid metabolism on proteomic and metabolomic levels as well as on gut microbiome in both mouse models. This will be correlated with metabolomic data from human ALS serum and cerebrospinal fluid samples to generate a machine learning tool, which will provide us with biomarkers that can help visualize disease progression and treatment efficacy as well as categorize ALS patients into subgroups, thus optimizing/individualizing the treatment. 2N s innovative treatment strategy targets a potential root cause of the ALS instead of only targeting the downstream mechanisms as the current standard-of-care treatment options, such as Rilutek and Radicava, do. With this comprehensive and unique approach, 2N differentiates itself from others and with essentially no direct competition. We believe that this change of paradigm of ALS and subsequent change in treatment strategy can be used to develop a new therapy for ALS by relieving disease symptoms and prolonging life expectancy beyond what is currently possible. Such discoveries may greatly benefit patient quality of life and improved public health by reducing the burden of a currently incurable and lethal degenerative disease. Furthermore, the proposed project will significantly impact biomarker identification with focus on alterations in the glucose and lipid metabolism that can be used as predictors of disease onset, disease progression, and therapeutic efficacy.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210091
Entities
People
- John Nieland
Organizations
- United States Army