Abstract: The invention provides targeting RNA, single guide RNA, tracrRNA, crisprRNA and expression vectors for use in CRISPR activation (CRISPRa) methods for the treatment of neurological disorders and diseases, in particular epilepsy and pain. In some preferred embodiments, a combinatorial gene therapy approach is used, wherein expression of multiple endogenous human genes are increased in a subject, in order to achieve a greater rescue of seizures and/or behavioural deficits, and restore physiological brain function.

Abstract: The invention provides expression vectors or vector systems comprising a polynucleotide sequence encoding a polypeptide, wherein the gene is operably linked to a neuronal activity-dependent promoter suitable to drive expression of the gene product in a subject’s neural cells. The features of the expression vectors combine to advantageously improve the treatment of a neurological disorder associated with neuronal hyperexcitability in a subject. The invention also provides the expression vectors or vector systems for use in related methods of treatment, as well as viral particles, cells, kits and methods using the expression vectors or vector systems.