Treatment of Sialic Acid Deficiency May Correct a Degenerative Muscle Disorder

Researchers working on the rare degenerative muscle disease HIBM (hereditary inclusion body myopathy) have genetically engineered a line of mice to express a mutated gene that prevents synthesis of sialic acid, a critical sugar required for muscle development and kidney function.

The mutant mice carry the M712T mutation in the GNE gene, which codes for the key enzyme of sialic acid biosynthesis, uridine diphospho–N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase. The lack of this enzyme results in a kidney condition that causes newborn mice to die within a few days after birth. "We were surprised that the HIBM mutation had such a detrimental impact on kidney function in the transgenic mice,” said senior author Dr. Marian Huizing, an investigator at the [U.S.] National Human Genome Research Institute (Bethesda, MD, USA). "Structural elements in the kidney that are important for filtering waste from the blood in these animals were severely impaired, and we linked this to sialic acid deficiency. This outcome demonstrates the significance of the ability of the body to synthesize sialic acid for kidney development and function.”

To counter the lack of sialic acid, the investigators treated pregnant mutant mice with N-acetylmannosamine (ManNAc), a sialic acid precursor. Results published in the June 2007 issue of the Journal of Clinical Investigation revealed that sialic acid production was improved in fetuses, and although smaller than normal mice, the offspring displayed significantly improved kidney function. So far, none of the treated mice have displayed symptoms similar to HIBM.

The improvement seen with ManNAc treatment in mice has prompted the investigators to schedule a human clinical trial of ManNAc for HIBM to begin in late summer or early fall of 2007.


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National Human Genome Research Institute