A novel gene therapy approach using antisense oligonucleotides to modulate the production of specific isoforms of CACNA1C might provide a new strategy to treat a severe neurodevelopmental disorder. CACNA1C codes for the α1C subunit of the L-type voltage-gated calcium channel Ca_v1.2. Autosomal dominant mutations in CACNA1C cause Timothy syndrome, a rare disease characterized by multisystemic defects and malformations, autism, epilepsy and other neurodevelopmental problems as well as a severe and life-threatening cardiac involvement in the form of a long QT syndrome.

Patients with Timothy syndrome type 1 carry the specific heterozygous missense variant c.1216G>A in the alternatively spliced exon 8A of CACNA1C. This variant promotes inclusion of the mutated exon 8A in splicing. Conferring a gain of function of the protein, the variant results in delayed channel inactivation and increased calcium entry into the cell, leading to enhanced neural excitability. In a study now published in Nature, a team of researchers developed antisense oligonucleotides (ASO) that decrease exon 8A inclusion in neural cells and effect a switch to exon 8 utilization. Their experiments in patient-derived cell models and in rats transplanted with human neurons demonstrated that ASO administration effectively rescued delayed calcium channel inactivation and changes in calcium entry into the cell.