Genome Editing for Personalized Medicine

Gene deficiency (haploinsufficiency) characterizes many forms of epilepsy and ASD. In this context, we aim at rebalancing haploinsufficiency by enhancing transcription of the remaining functional gene copy. To this end, we have repurposed the CRISPR/Cas9 technology for regulating gene expression for both hereditable diseases and personalized medicine. We can direct the RNA-guided transcription activator dCas9-VP64 to the promoter region of epilepsy/ASD genes to fine-tune their expression. In particular, the transcription of single alleles in heterozygous mice can be enhanced in a dose-dependent fashion to match the expression levels found in WT mice. We will test whether the epilepsy and ASD-related abnormalities of haploinsufficient mice can be reversed by CRISPR/Cas9-mediated activation of transcription. In the context of ataxia or epilepsy (Dravet syndrome), we have recently succeeded in modifying ‘at whim’ the splicing composition of presynaptic calcium channels or sodium channels NaV1.1 with CRISPR/Cas9. This represents a completely new application of the CRISPR/Cas9 technology, and provides us with a unique means to target simultaneously multiple splicing events in any gene(s) of interest and develop a gene therapy for invalidating neurological diseases.

 Genome1

People: Cingolani