In the new study, the researchers tested various therapies in four groups of newborn mice with infantile Batten disease. One received only gene therapy; another received only bone marrow transplants; a third was treated with gene therapy and bone marrow transplants; and a fourth group received no treatment. As a comparison, the study included healthy mice without the disorder.

Gene therapy to replace the PPT1 enzyme was delivered directly into the brain. Bone marrow transplants were given with the intent that donor cells would migrate to the brain and deliver additional enzyme to regions of the brain not reached by gene therapy.

But that’s not what happened, Sands says. Although gene therapy delivered relatively high levels of PPT1 enzyme, the bone marrow transplants did not supply any additional enzyme. Rather, he and his colleagues discovered that mice receiving both therapies experienced a dramatic reduction in brain inflammation.

“We suspect that the normal immune cells from the bone marrow transplant substantially reduce inflammation in the brain because we just don’t see much of it in mice that got both therapies,” Sands says. “This helps the PPT1 enzyme to do its job inside cells.”

The study’s results show no increase in life span for mice receiving bone marrow transplantation alone compared to untreated mice – animals in both groups lived a median of 8.9 months. Mice that got only gene therapy lived 13.5 months, while those that got the combination therapy lived for 18.5 months.

The researchers noted similar effects of the therapies when they evaluated motor function. By 6 months, both untreated mice and those that received only a bone marrow transplant had experienced significant declines in motor skills. Mice that got gene therapy alone experienced a decline in motor function beginning at 10 months, and in those that got combination therapy, motor skills did not begin to decline until 13 months and did so more gradually than in the other mice.

Mice that got the combination therapy also had higher levels of active PPT1 enzyme in the brain, a thicker cerebral cortex and fewer accumulated proteins in brain cells, all indicators that the treatment is working.

Sands is now repeating the experiment and investigating other ways to reduce inflammation in the brain that would not involve the risks of a bone marrow transplant. One possibility, he says, involves anti-inflammatory drugs that have effects in the brain.

“We may be able to achieve the same results with a less invasive anti-inflammatory treatment,” Sands says. “We’re very excited now to move forward.”

The research is supported by the National Institutes of Health (NIH), Ruth L. Kirschstein NRSA Fellowship, The Wellcome Trust, Batten Disease Family Association, the Batten Disease Support and Research Association and the Bletsoe Family.

Macauley SL, Roberts MS, Wong AM, McSloy F, Reddy AS, Cooper JD and Sands MS. Synergisitc effects of CNS-directed gene therapy and bone marrow transplantation in the murine model of infantile neuronal ceroid lipofuscinosis. Annals of Neurology. Online ahead of print, Feb. 24, 2012.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

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By Caroline Arbanas
Washington University in St. Louis