Exploring a Potential New Therapy for Fatal Canavan Disease 

Testing a new approach to treating the fatal inherited condition in infants and children called ‘Canavan” disease
David Pleasure, M.D.

Shriner's Hospital for Children, Sacramento, CA, Department of Neurology

Grant Program:

Clinical Neuroscience Research

Funded in:

April 2017, for 3 years

Funding Amount:


Lay Summary

Exploring a potential new therapy for fatal Canavan disease 

Investigators will test in a mouse model a new approach to treating the fatal inherited condition in infants and children called ‘Canavan” disease. If promising, the research is anticipated to lead to human clinical testing of this first potential therapy.

Canavan disease is currently untreatable and kills during infancy or early childhood. It results from a genetic mutation that allows excessive amounts of an amino acid called NAA to build up in the brain. The mutated gene fails to produce an enzyme that ordinarily metabolizes (converts into energy) NAA in the brain. Instead, NAA accumulates and destroys the brain’s “white matter,” the communication cables that connect one region to another. Specifically, NAA damages the myelin sheath that insulates the communication cables, called “axons.” When the axons become “demyelinated,” they can no longer effectively send electrochemical messages from one brain cell to another. The disease progresses rapidly as the infants fail to develop muscle strength and tone, cannot keep their heads up, and cannot feed properly .

The disease occurs when both parents carry the gene and pass it on to the fetus. The probability for each pregnancy that the infant will be affected is 25 percent. Attempts to modify the mutated gene so that it produces the enzyme needed to metabolize NAA have to date produced only minor clinical benefits. So, the investigators are trying the converse. They are working to modify a gene that produces an enzyme that is needed to make (synthesize ) NAA. This way, only small amounts NAA would be synthesized and this might limit elevations of NAA in the brain and prevent its accumulation.

They are using a harmless viral vector that carries the means for modifying the gene and injecting them into the ventricles in the mouse brain. Their initial research in mice indicates a beneficial effect of this genetic modification on the brain’s white matter and on motor performance in the mice. The investigators now will expand this study to additional mice that are followed over a longer period. If promising, the investigators then will test this experimental gene modification treatment it in rats. Success in both animal models would lead to the first human clinical testing in affected infants.

Significance: If successful, this genetic modification approach may lead to the first treatment for fatal Canavan disease.


Canavan's Disease treatment

The goal of this project is to devise an effective treatment for Canavan disease, a recessively inherited leukodystrophy caused by brain aspartoacylase deficiency and characterized by developmental delay, elevated brain N-acetyl-L-aspartate (NAA), and spongiform degeneration of brain white matter. We reported in 2015 that genetic disruption of both alleles of Nat8l, which encodes neuronal N-acetyltransferase 8-like, a neuronal enzyme required for brain NAA synthesis, prevents mice that are deficient in aspartoacylase from developing spongiform leukodystrophy. This result indicates that leukodystrophy in aspartoacylase-deficient mice, and likely also in Canavan disease, is at least in large part attributable to a neurotoxic effect of elevated brain NAA. Our present goal is to devise a potentially translatable strategy to inhibit brain Nat8l activity, thereby preventing NAA elevation and leukodystrophy in aspartoacylase-deficient mice.

Investigator Biographies

David Pleasure, M.D.

David Pleasure MD, a neurologist, is a Distinguished Professor of Neurology and Pediatrics at the University of California Davis (UC Davis), where he directs the Institute for Pediatric Regenerative Medicine (website iprmd.org), a research consortium between the UC Davis School of Medicine and the Shriners Hospitals for Children Northern California.  His research focuses on inherited and acquired diseases of white matter.