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.
Alzheimer'srelated dementia will effect over 15 million americans and cost near $200 billion/year by 2015. Nemametrix is developing humanized animal models to discover therapeutics for the Alzheimer'sDiseaseRelated Dementias (ADRD) of Frontotemporal Dementia (FTD). Leads discovered are developed for use by clinicians to treat patients with dementia.
