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March 22, 2017

Malaria drug may help kids with rare genetic disorder, SickKids study finds

TORONTO – A drug commonly used to treat malaria may prevent neurodegeneration in kids with rare genetic disorder called Zellweger Spectrum Disorder, new research finds. The study was led by researchers at The Hospital for Sick Children (SickKids) and is published in the journal Autophagy.

Also known as Peroxisome Biogenesis Disorder, Zellweger Spectrum Disorder is a group of rare, childhood neurodegenerative diseases that are characterized by the absence or reduction of a part of our cells called peroxisomes. Peroxisomes are organelles involved in the removal of toxins that damage cells, and the making of specialized fats needed for brain formation.

Zellweger Spectrum Disorder affects 1 in 50,000 children worldwide. SickKids sees about two cases a year. Children with the severe form of the disease typically die within the first year of life, while those with the less severe form may live into early adulthood. The less severe form, which makes up almost 70 per cent of all diagnosed cases, is caused by a mutation in a gene called PEX1.

It was thought that a mutation in PEX1 caused the failure to make peroxisomes, but this study reveals that this is not the case. Researchers found that this gene plays a role in peroxisome quality control; more specifically they describe how the PEX1 gene removes a marker on peroxisomes that tells the cells to degrade or dispose of this important organelle. Therefore cells with a mutant PEX1 cannot remove this marker and results in the disposal of good peroxisomes.

“Our findings represent a major paradigm shift in the understanding of peroxisomes. It’s not that the peroxisomes are not being formed in children with PBD, but rather, without this gene the peroxisomes are more rapidly degraded,” says Dr. Peter Kim, Principal Investigator of the study and Senior Scientist in Cell Biology at SickKids. “This suggest that preventing peroxisome degradation could be a strategy to treat individuals with mutation in this gene.”

An FDA-approved drug that is currently used to treat malaria, called Chloroquine, is already known to inhibit peroxisome degradation, so the research team tested it in the lab on cells from patients with Zellweger syndrome. They found that this drug not only returns peroxisome numbers but also improves the function.

:   This image shows how treatment with the drug, Chloroquine, improves peroxisome numbers in cells of individuals with the mutated PEX1 gene.
This image shows how treatment with the drug, Chloroquine, improves peroxisome numbers in cells of individuals with the mutated PEX1 gene. Image A shows peroxisomes in a healthy individuals; Image B and C show peroxisomes in cells with the mutated PEX1 gene. The number of peroxisomes in the mutated PEX1 cell is less than those found in normal cells (compare A to B). The mutated PEX1 cells treated with chloroquine show an increase in peroxisome numbers (Compare B to C).

“This research provides the necessary evidence to explore the use of Chloroquine for treatment in patients with Zellweger syndrome in the near future,” says Kim, who is also Associate Professor in the Department of Biochemistry at the University of Toronto. “Currently, there is no real treatment for Zellwegger spectrum disorder. There are many different symptoms that are treated individually. Our findings show that we may be able to treat many of these symptoms with just one drug. It also suggests that this treatment could decrease neurodegeneration, improve liver function and improve the quality of life for these patients.”

This study was funded by the Canadian Institutes of Health Research and SickKids Foundation. The project investigators collaborated with the Industry Partnerships and Commercialization Office at SickKids.

It is an example of how SickKids is contributing to making Ontario Healthier, Wealthier and Smarter www.healthierwealthiersmarter.ca.

About The Hospital for Sick Children
The Hospital for Sick Children (SickKids) is recognized as one of the world’s foremost paediatric health-care institutions and is Canada’s leading centre dedicated to advancing children’s health through the integration of patient care, research and education. Founded in 1875 and affiliated with the University of Toronto, SickKids is one of Canada’s most research-intensive hospitals and has generated discoveries that have helped children globally.  Its mission is to provide the best in complex and specialized child and family-centred care; pioneer scientific and clinical advancements; share expertise; foster an academic environment that nurtures health-care professionals; and champion an accessible, comprehensive and sustainable child health system. SickKids is proud of its vision for Healthier Children. A Better World. For more information, please visit www.sickkids.ca. Follow us on Twitter (@SickKidsNews) and Instagram (@SickKidsToronto).

Media contacts:

Caitlin Johannesson
The Hospital for Sick Children
416-813-7654, ext. 201436
caitlin.johannesson@sickkids.ca

Matet Nebres
The Hospital for Sick Children
416-813-6380
matet.nebres@sickkids.ca