Repurposed Drug Could Treat Childhood Genetic Diseases

Coloforsin increased survival in mouse models of Krabbe disease.

New research shows that certain marketed drugs could potentially be repurposed to treat severe genetic childhood diseases.

Lysosomal storage disorders (LSDs) are caused by disruptions in the lysosomes, which are known as the stomach of the cell, because it can process unwanted materials into useful substances. This group of disorders include Krabbe disease, Gaucher disease, metachromatic leukodystrophy, and 40 other conditions. Aggressive forms of these diseases can cause death within years of birth, and there is currently no cure.

In a new study published by PLOS Biology, researchers discovered how specific toxic waste products in patients with LSDs cause dysfunction in affected cells. They also found that marketed drugs can potentially overcome the build-up of cellular toxicities, which could provide patients with a novel treatment option.

During the study, the researchers demonstrated that lysosomes are typically more acidic compared with other parts of the cell, and the accumulation of toxic substances, caused by LSDs, disrupt the maintenance of the acidic environment of the lysosomes.

They also found that restoring normal acidity levels in the lysosomes via drug treatment was able to prevent multiple disruptions of lysosome function and was able to maintain processes critical to cell function, such as division and survival, according to the study.

In a mouse model of Krabbe disease, the drug coloforsin was able to increase survival comparably to studies involving gene therapy. Currently, the drug is approved in Japan to treat heart disease. Increased survival was still seen, although coloforsin therapy was initiated later than necessary for gene therapy, the researchers reported.

Decreased brain damage and increased quality of life was also seen in mice models treated with the drug, according to the study. These findings were the desired outcomes for a novel treatment for children with LSDs, and suggest that coloforsin could be repurposed to treat these disorders.

If these results can be proven in humans, repurposed drugs could potentially be used to treat patients with LSDs while gene therapy options are pursued. Since lysosome dysfunction is also linked to other diseases, such as diabetes and macular degeneration, these new drugs may also provide novel treatment options for various conditions.

"One of the great challenges in these diseases is that they are both rare and come in many different varieties, and advances have tended to focus on single diseases," said corresponding author Mark Noble, PhD. "In contrast, our findings suggest our treatments will be relevant to multiple disorders. Also, we saw benefits of our treatment even without needing to correct the underlying genetic defects. That gives us great hope that we could combine our treatments with other candidate approaches to gain additional benefits."