Testing Lifespan/Healthspan Pharmacological Interventions in Humanized C. elegans Knock-In Models of Dementia

Nemametrix, Inc., Eugene OR

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Linked publications & trials

Abstract

By 2050, over 15 million people in the USA will be diagnosed with Alzheimer's­related dementia at an annual treatment cost near $200 billion. To contain the escalation in healthcare costs, new treatments are needed to relieve the underlying genetic causes and risk factors leading to dementia onset. In simple animal models, drugs have been found that lead to lifespan extension. Yet the underlying genetic mechanisms as drug targets for Alzheimer's­related dementia remain elusive. In this SBIR proposal, humanized animal models are created to model genetic disorders of the Frontotemporal Dementia (FTD) component of Alzheimer's­Disease­Related Dementias (ADRD). Four FTD genes are targeted for humanization (MAPT, GRN, C9orf72, and TARDBP) in the C. elegans animal model. The procedure for humanization resulting gene­specific replacement with human cDNA. Using a CRISPR­based Gene­swap technique, a sequence­optimized human gene is inserted as a replacement of an orthologous gene in the genome of the animal model. Each humanized animal creates a platform for installing and profiling the functional consequence of pathogenic variants. The variants causing deviant phenotypes are screened for the capacity of longevity­associated molecules to restore wildtype phenotype. If FTD model creation and compound screening reveal a restorative capacity, the assay system can then be used for discovery of novel therapeutic molecules. Leads discovered are commercialized by internal or externally­licensed drug development into therapeutics for treating FTD disease.