Grant: DRA : Canada Graduate Research Scholarship - Doctoral Program (CGRS D)

The white matter of the brain contains myelin, a specialized cellular membrane that ensheathes neurons within the brain. Myelin is composed of many different proteins and its' proper formation is critical to maintaining normal physiological functions. The gene CLDN11 encodes for the claudin-11 protein, a protein abundant in myelin. Recently, there have been several cases reported of patients with an early-onset neurodegenerative disease harbouring rare genetic variants in one of the two copies of their CLDN11 gene. The variants lead to the predicted extension of the claudin-11 protein, resulting in an abnormal protein being produced. Patients with these genetic variants suffer from hypomyelinating leukodystrophy (HLD). Currently, most treatments for leukodystrophies remain symptomatic management, and to date, there is no curative treatment for claudin-11 based HLDs. Antisense oligonucleotide (ASO) therapy is a gene therapy approach that specifically targets and reduces specific mRNA levels. Since the claudin11-based-HLD patients retain one normal copy of the CLDN11 gene, the use of ASOs to reduce the variant claudin-11 protein may be a promising therapeutic approach, potentially restoring function to the normal protein present. An additional therapeutic approach is the use of base editors (BEs), a tool that can specifically introduce a single nucleotide change into the genome. One of the CLDN11 variants is amenable to BE as a therapeutic strategy to restore the genetic variant to the nucleotide typically present. This is an attractive therapeutic approach as it is possible to permanently correct the patient's mutation, thus potentially curing the disease. Through testing in both human cell models and mouse models of the disease, two therapeutic avenues will be explored: ASO treatment to reduce mutant claudin-11 and base editing to correct the underlying mutation.