Category: Other leukodystrophy

Despite the increasing rate of diagnosis enabled by next generation sequencing, the molecular basis underlying about half of leukodystrophies is unknown. Among recently discovered hereditary leukodystrophies, several pathogenic variants are located within genes that converge on a common pathway, thus it is possible that they share common underlying mechanisms.

HIKESHI Hypomyelinating Leukodystrophy (HHL) is a rare and devastating congenital disorder with infantile onset during the first year of life. Symptoms include poor growth, delayed motor milestones, central hypotonia and other psychomotor disabilities. HHL patients have an increased sensitivity to heat stress. Febrile illness often leads to an irreversible deterioration of the neurological condition, and may even lead to death. There is currently no curative treatment for HHL and the symptomatic treatments are focused on prevention of fever.

When a gene mutation causes a protein to be missing or faulty, gene therapy may be able to restore the normal function of that protein. This approach has been recently translated from basic research to the clinic, for the treatment of SMA, a devastating infantile neurological condition. Thus, a similar approach can be used to treat additional conditions, such as HLL and other leukodystrophies. However, in order to test this approach it is necessary to develop appropriate research models.

Animal models have been traditionally used for pre‐clinical research, but increasing evidence suggest that mice are different than humans, and therefore curing a mouse model in the lab often does not translate into the clinic. Therefore it is crucial to develop human‐based models that will better represent human physiology.

Here, we propose to use cutting‐edge techniques that include patient‐specific stem cells (termed iPSCs) and engineered Organ‐on‐Chip to generate a personalized Brain‐on‐Chip. This platform will be used to identify disease‐relevant phenotypes, which we will use for testing our gene therapy approach. Successful rescue of such phenotype will indicate that gene therapy should be tested in the clinic. The approach that we will apply in this research is focused on HHL, but it can be applied to additional leukodystrophies and other neurological conditions in the future.

Hypomyelinating leukodystrophy 16, also known as HLD16, is a rare genetic disorder that affects the development of myelin, the protective covering around nerve fibers in the brain. HLD16 is caused by a mutation in the gene TMEM106B. We genetically engineered mice in a way that they have the same mutation in TMEM106B that is found in human patients. We plan to investigate these mice to understand the disease and how the mutation in this gene, whose function is yet unknown, leads to this rare disease. This will help to develop future therapies and understand the function of TMEM106B in myelination.