SUMMARY Mutations in CaV2.1 pore-forming 1A subunit cause a spectrum of neurological diseases including epileptic encephalopathies (EE), familial hemiplegic migraine type 1 (FHM1), episodic ataxia type 2 (EA2), spinocerebellar ataxia type 6 (SCA6), and intellectual disability (ID). The ClinVar database has entries for >1000 CACNA1A mutations most of which (437) are classified as variants of unknown significance (VUS), pathogenic (137), or likely pathogenic (61). There are several challenges for efforts to develop effective therapies for CACNA1A channelopathies: 1) the large number of dmutations that give rise to disease make it unclear whether common therapies can be found; 2) the full scope of functional alterations due to individual mutations and how these relate to disease etiology are ambiguous; and 3) lack of novel therapeutics targeted to CaV2.1 functional deficiencies. We hypothesize that the hundreds of distinct CACNA1A mutations fall into a few discrete functional groups that can be targeted by novel bioengineered molecules tailored for each class. Our long-term objective is to gain an in-depth perspective on how distinct CACNA1A mutations give rise to a spectrum of neurological disorders and to develop molecules that can address the functional deficits as potential therapeutics. Here, we propose an inter-disciplinary, multi-level proposal spanning single-channel and whole-cell Ca2+ channel biophysics, patient- specific induced pluripotent stem cell neurons (hiPSC-neurons), mouse models of CACNA1A neurological disease, and development of corrective molecules. The breadth of the proposal is enabled by collaboration and combining resources between two labs− the Colecraft lab (Columbia University) has strong expertise in molecular physiology and biophysics of CaV channels and developing innovative tools to regulate their functional expression; the Rossignol lab (Montreal University) has expertise in generation and functional characterization of CACNA1A mouse models of neurological disease. Dr. Rossignol is a clinician-scientist with a cohort of CACNA1A patients who thus also brings a clinician’s perspective to the project. We propose three Aims all of which are supported by strong preliminary data. 1) Determine holistic functional impact of distinct CACNA1A mutations on recombinant CaV2.1 channels, and develop tailored approaches to correct different classes of mutations. 2) Develop human ipsc-neurons to model and elucidate mechanisms of CACNA1A channelopathies and to evaluate efficacy of novel potential therapeutic molecules. 3) Utilize mouse models to determine mechanisms of disease and evaluate efficacy of novel tailored approaches to treat disease.