JuvoBio Pharmaceuticals Inc. — Department of Health and Human Services SBIR Phase I: 101

Description

PROJECT SUMMARY We aim to establish a single cell RNAseq database of differentiating cortical neuronal progenitors NPCs and neurons derived from patient specific induced pluripotent stem cells iPSCs for neuro developmental diseases NDDs The database will also include data on differentiation morphology formation and functionality of synapses annotations of analytical findings and will be supported by the most advanced single cell RNAseq bioinformatics tools We will provide all this together with corresponding NPCs and neurons for research reagents as tool to support academic research and drug discovery for NDDs in the field One in children born in are diagnosed with Autism Spectrum Disorder ASD a public health priority in the US Genetic predispositions in ASD are thought to contribute to the primary pathology by altering neuronal development evidenced partly by altered gene expressions Patient specific induced pluripotent stem cells iPSCs have been shown to recapitulate specific disease phenotypes through the neurogenic process and can serve as effective disease models Hence single cell RNAseq along the accessible and controlled process of differentiating ASD specific iPSCs into neural progenitors and subtypes of neurons can provide insights into the temporal and multi lineage dimensions of ASD pathogenesis and biomarkers for diagnostics progression and therapeutics discovery Copy number variants CNVS at q is a prominent risk factor for neurological disorders including ASD epilepsy and schizophrenia q q duplication triplication represent the most common CNVs in patients with ASD up to Duplications and microdeletions can both lead to the same disorders suggesting the importance of this region in normal neurological functions and the necessity to study the impact of both duplications and deletions for a full understanding of the mechanisms Phase I utilizes four q duplication iPSC lines from ASD patients and two control iPSC lines to Aim Characterize neural differentiation of ASD and control iPSC derived neurons Differentiate iPSCs into cortical NPCs glutamatergic and GABAergic subtypes Identify deficits in ASD lines through morphological studies and structural analyses of synapses Aim Generate single cell RNAseq datasets of differentiating NPCs and neuronal subtypes at nine time points during differentiation Aim Perform bioinformatics analyses Reconstitute the molecular dynamics underlying neuronal differentiation Validate experimental conditions including sampling frequency and number of cells Identify validate molecular signatures underlying q duplication s impact on neuronal differentiation and functions Phase II utilize the experimental conditions established here to generate single cell RNAseq datasets from multiple ASD iPSC lines that harbor different genetic mutations to be included in the database build database structure and user interface and seek to identify aberrant differentiation and functional development caused by ASD mutations as well as genes and pathways that are commonly and differentially affected across multiple ASD mutations We will devote resources to annotate the database with our own findings and those that are published by peers to enhance its utility to subscribers PROJECT NARRATIVE TEMPORAL SINGLE CELL RNASEQ TO IDENTIFY GENES AND PATHWAYS AFFECTED BY Q DUPLICATION IN AUTISM IPSC DERIVED DIFFERENTIATING CORTICAL NEURONS One in children born in are diagnosed with Autism Spectrum Disorder ASD the fastest growing and most prevalent form of developmental disabilities and a national health priority in the United States JuvoBio Pharmaceuticals is developing an innovative tool that can better understand the mechanism of ASD pathogenesis and of its diverse clinical presentation and progression This project helps to identify biomarkers that can be used as diagnostics markers for disease progression and drug target for discovering new therapeutics