A new approach to treating neurodegenerative disorders including Krabbe disease

Dr Farah Lamiable-Oulaidi, Victoria University

Scientists at Te Herenga Waka—Victoria University of Wellington’s Ferrier Research Institute have received funding for ground-breaking research designed to find new treatments for neurodegenerative disorders. Dr Farah Lamiable-Oulaidi and her team have received a grant from Cure Kids to facilitate the development of molecular chaperones designed to reverse the effects of genetic disorders that cause the diseases.

A fresh approach to treating neurodegenerative disorders

Neurodegenerative disorders occur when nerve cells in the brain and surrounding nervous system gradually stop working and die. Alzheimer’s and Parkinson’s disease are two of the most common. Krabbe disease (KD) is a much rarer inherited neurodegenerative disorder that leads to death within the first few years of life.

Understanding Krabbe disease

Krabbe disease is caused by gene mutations that mainly result in misfolded GALC proteins. This leads to a lack of the enzyme β-galactosylcerebrosidase, which causes the lipid psychosine to reach levels that are toxic for nerve cells. Unfortunately, there is currently no treatment for this fatal disorder and therapeutic strategies are limited by the highly selective barrier between the brain and the blood stream.

Designing a Goldilocks drug

Dr Lamiable-Oulaidi and a team from Te Herenga Waka—Victoria University of Wellington are investigating an exciting new approach to treat neurodegenerative diseases caused by misfolded proteins. It involves combining two proven techniques, chaperone-mediated therapy (CMT) and transition-state analysis, which could lead to new drug candidates for pharmaceutical development.

CMT uses a small molecule called a pharmacological chaperone (PC) to selectively bind to the enzyme active site and enable protein refolding. Once transported to its site of utility, the PC is displaced and the refolded enzyme breaks down the accumulated lipids, reducing the effects of the disease. The challenge is finding a Goldilocks PC (not too strong, not too weak, but just right). A PC that binds tightly enough to the enzyme’s active site to promote refolding and trafficking but not too tightly so it can be displaced. To achieve this, Dr Lamiable-Oulaidi and her team will use enzymatic transition state (TS) analysis. This technique has been successfully used to design powerful enzyme inhibitors but has never been applied to the design of PCs. Their work will begin with the enzyme at the heart of Krabbe disease and then be applied to develop PCs for other neurodegenerative disorders.

Cure Kids is funding the development of PC targets

A grant from Cure Kids is contributing to this ground-breaking research into designing tailormade PCs for treating devastating neurodegenerative disorders like KD. By funding computational dynamics studies to refine PC design, Cure Kids greatly support a novel approach towards a treatment for Krabbe disease.