Mouse study shows potential for gene therapy in Alport syndrome


December 19, 2013
Health

A new study in mice suggests that gene therapy one day may be a viable treatment for Alport syndrome, an inherited disease that leads to kidney failure. The research, by scientists at Washington University School of Medicine in St. Louis, is available online in theJournal of the American Society of Nephrology.

Alport syndrome affects one in 5,000 people and is more severe in men than in women. The disease is caused by mutations in any one of three genes that collectively produce a special type of collagen. This collagen is a critical component of a membrane in the kidney’s glomeruli, where waste is filtered from the blood into urine. Disrupting any of these genes alters the collagen network, leaving the so-called basement membrane in the glomeruli with defects that make it unable to adequately filter waste.

Early treatment with certain blood pressure medications can slow progression of the syndrome, but many patients develop end-stage kidney disease by the time they reach young adulthood. At that point, the standard treatment is either a kidney transplant or dialysis, with the goal of an eventual kidney transplant.

Senior author Jeffrey Miner, PhD, and his colleagues asked whether it is possible in mice with Alport syndrome to repair a defective basement membrane once it is formed and functioning abnormally. Their work indicates that the therapy can restore, at least partially, the missing collagen network, thereby slowing progression of kidney disease and extending life span.

As part of the research, Miner and his colleagues demonstrated they could induce expression of a missing collagen gene 21 days after the mice were born.

“This time point is important because it is equivalent in age to preadolescence in humans,” explained Miner, a professor of medicine and of cell biology and physiology. “Most people with Alport syndrome have little or no scarring of the kidneys at that time, so correcting the basement membrane defect could prevent loss of kidney function.”

When activated, the gene produced enough collagen to repair the basement membrane, although some irregularities persisted.

Without the therapy, Alport mice survived no longer than 32 weeks, compared with treated mice, which typically lived twice as long. Several survived for well over a year, clearly benefiting from the therapy.

Mouse study shows potential for gene therapy in Alport syndrome“Even with treatment, there were some abnormalities in the basement membrane and in kidney function,” Miner said. “But the damage was not significant enough to cause end-stage kidney disease. If the same treatment were successfully translated to patients, it could postpone the need for dialysis and buy patients more time to find the right kidney donor, and that could make a huge difference.”

Much more research remains, he cautioned, but the new study suggests that some form of gene therapy eventually could be used as a treatment for patients with Alport syndrome.

The research is funded by the National Institute of Diabetes and Digestive and Kidney Diseases at the National Institutes of Health (NIH), the Alport Syndrome Foundation and the O’Brien Center for Kidney Disease Research.

Lin X, Suh J, Go G, Miner J. Feasibility of repairing glomerular basement membrane defects in Alport syndrome. Journal of the American Society of Nephrology. Nov. 21, 2013.

Mouse study shows potential for gene therapy in Alport syndrome

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