ACURASTEM INC — Department of Health and Human Services SBIR Phase I: NIA

Description

Preserving cellular aspects of aging in patient specific models of ALS Project Summary Induced pluripotent stem cell iPSC biology holds great promise for human in vitro neurodegenerative disease modeling because these cells can give rise to any cell in the human brain a living virtual brain amenable to experimental manipulation having the exact same genetic makeup as individual patients and displaying neurodegenerative phenotypes previously identified in postmortem and clinical samples These patient specific in vitro testing systems enable target discovery drug screening and therapeutic proof of concept studies in patient cells much earlier in the translational process than is currently possible Despite these unique advantages the preservation of age as a key pathogenic risk factor is presently a major limitation of these systems This is in part due to the loss of age related characteristics in cells that are rejuvenated to an embryonic state and to deficiencies in the differentiation protocols that are unable to produce mature neurons from embryonic cells The direct transcription factor mediated reprogramming also known as lineage conversion of patient fibroblasts into induced motor neurons represents an alternative approach for generating human neurons in vitro New data from our lab our collaborators and others show that neurons generated through lineage conversion better retain age related and disease associated deficits In this year feasibility study we will compare motor neurons generated by lineage conversion from fibroblasts fib MNs with those generated by directed differentiation from iPSCs reprogrammed from the same fibroblast samples iPSC MNs The fibroblast samples are from patients having the GGGGCC hexanucleotide repeat expansion mutation in the C ORF gene which is known to cause a form of amyotrophic lateral sclerosis ALS and frontotemporal dementia and matched controls Our st hypothesis is that fib MN transcriptomes will be significantly more similar to those of post mortem tissue and those from ALS patients Our collaborator Verge Genomics has created an innovative big data driven ALS gene expression signature using public and proprietary gene expression data from ALS relevant studies that we will use in the project Nucleocytoplasmic transport defects have emerged as one phenotype where both age and C ALS related differences have been identified Therefore our nd hypothesis is that fib MNs will have significantly more pronounced age related nucleocytoplasmic transport defects than iPSC MNs as measured by immunofluorescence confocal microscopy Taken together these two studies would prove the principle that fib MNs create superior ALS in vitro testing systems retaining important disease relevant aspects of aging having tremendous impact on the iPSC banking and disease modeling fields AcuraStem Inc develops human cell models and assays for preclinical human validation of its own CNS therapeutics as well as those of its development partners Preserving cellular aspects of aging in patient specific models of ALS Project Narrative Human in vitro testing systems enable target discovery drug screening and therapeutic proof of concept studies in patient cells much earlier in the translational process than is currently possible The preservation of age as a key pathogenic risk factor is presently a major limitation of these systems In this project we propose new methods to overcome these limitations and create a human in vitro testing system for amyotrophic lateral sclerosis ALS that preserves disease relevant aspects of aging