CRISPR knockout of HRE sequences in the C9orf72 gene to treat ALS, FTD, and HDL2

Abstract

Amyotrophic lateral sclerosis (ALS), familial frontotemporal dementia (FTD), and phenotypic Huntington syndrome-like disease (HDL2) have in common multiple hexanucleotide repeat expansions (HREs), in the C9orf72 gene. The C9orf72 protein aids in sending and receiving signals in multiple neurons. The C9orf72 protein is found primarily expressed in the brain and specific neurons, especially in the cerebral cortex. In ALS, FTD, and HDL2, the gene has a repeat sequence GGGGCC that is found in many patients with familial neurodegenerative conditions, resulting in the loss of function of many patients' motor neurons. The repeat sequence causes reduced production of the C9orf72 protein, called haploinsufficiency, and simultaneously a gain-of-function mutation by producing toxic dipeptide proteins, and excess RNA foci (RNA toxicity) in the brain. Different gene editing techniques in vitro and in vivo have shown the successful knockout of genes in the brain as well as on the C9orf72 gene and the connection to ALS, FTD, and Huntington-like syndrome in mice. CRISPR is a gene-editing tool used to target HREs. This review will focus on knocking down/out the HREs of the C9orf72 gene using various delivery strategies. Targeting the C9orf72 gene HREs, it would be expected that a decrease in protein aggregations that affect motor neurons, be able to prevent protein haploinsufficiency and prevent RNA toxicity, which are the main factors of these three neurodegenerative diseases. Using gene editing, treatment may be possible for patients with familial ALS, FTD, and HDL2 with the HRE sequences in the C9orf72 gene.