CACNA1A-related ataxia: functional characterization of clinically severe variants for drug repurposing

Goals:
- Evaluate the impact of these severe recurrent variants in a wide ataxic population, in order to define a clinical signature for the subjects at risk for severe episodes that can be life threatening
- Analyze CACNA1A patient-derived cells reprogrammed into neuronal cell lines (iPSCs), performing biochemical, morphometric, and electrophysiological studies.
- Test the efficacy (on cellular phenotypic rescue) of compounds empirically used in CACNA1A mutated patients to obtain "variant-tailored" therapies.

Description:
CACNA1A (Cav2.1, alpha-1A subunit of P/Q-type calcium channel) missense causing variants, are responsible for cerebellar ataxia associated with other neurological symptoms (hemiplegic migraine, seizures) that in most severe cases can evolve to confusional and coma-like states. We have selected CACNA1A variants (both gain and loss of function) with variable spectrum of phenotypes including a subset of clinically severe variants (e.g. NM_001127221: p.T666M, p.V1393M, p.S218L).

We propose:
(1) to evaluate the impact of these severe recurrent variants in a wide ataxic population made available by the ARCA and SCA global consortium, in order to define a clinical signature for the subjects at risk for severe episodes that can be life threatening.
(2) to analyze CACNA1A patient-derived cells reprogrammed into neuronal cell lines (iPSCs), performing biochemical (calcium imaging, protein expression) morphometric (dendritic development) and electrophysiological (spontaneous neurotransmission, neuronal excitability) studies.
(3) to test the efficacy (on cellular phenotypic rescue) of compounds empirically used in CACNA1A mutated patients such as riluzole and TRH derivatives (Ishida et al. 2016), 4-Aminopyridine and Acetyl-DL-leucine (Schniepp et al. 2016) and other compounds that will be identified by chemical library screening for functional rescue.

Cohorts used CACNA1A-related ataxia
Funding available? To be sought
Trial readiness category 1 - basic prerequisites for trial readiness

Contact persons:
Ginevra Zanni
Unit of Muscular and Neurodegenerative disorders, Dept of Neurosciences, Bambino Gesù Children’s Hospital, Rome, Italy

Enrico Bertini
Unit of Muscular and Neurodegenerative disorders, Dept of Neurosciences, Bambino Gesù Children’s Hospital, Rome, Italy

Further project partners:
Valentina Muto
Bambino Gesù Children’s Hospital, Rome, Italy
Marco Tartaglia
Bambino Gesù Children’s Hospital, Rome, Italy