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2-track therapy shows promise in study of Alzheimer’s in mice

By Meg Tirrell
Bloomberg News / January 7, 2010

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NEW YORK - Alzheimer’s disease may be better treated with a cocktail of therapies that limit production of the plaque that impairs the brain rather than with a single treatment, a study in mice suggests.

The combination approach preserved memory with few side effects, something individual treatment methods haven’t been able to do as well, researchers at Johns Hopkins University School of Medicine said in a report published yesterday in the journal Science Translational Medicine.

There is no cure yet for Alzheimer’s, a disease that attacks the brain and causes memory loss that can devolve into severe cognitive decline. It affects an estimated 30 million people worldwide and was the sixth-leading cause of death in the United States in 2007, according to the Centers for Disease Control and Prevention in Atlanta. Scientists suspect Alzheimer’s may be caused by a protein called amyloid beta, generated by two enzymes that drugmakers have been targeting individually with experimental treatments.

“The idea is if you can identify compounds or drugs that inhibit these enzymes, you’ll be able to slow down the progression of the disease,’’ said Philip Wong, a professor in the pathology and neuroscience departments at Johns Hopkins who was a senior author of the study. “One of the major issues is side effects.’’

Two enzymes known to spur formation of amyloid beta that afflicts brain function are beta-secretase and gamma-secretase, both targets in Wong’s study of mice.

Drugmakers such as Eli Lilly & Co., GlaxoSmithKline, Pfizer, and Bristol-Myers Squibb are working on Alzheimer’s treatments that aim to inhibit either the beta- or gamma-secretase enzyme, Wong said.

The idea of targeting both enzymes simultaneously is “completely novel,’’ Wong said. Drugs have to be approved for use individually before they could be combined, pushing the prospect of human testing with a potential cocktail years off, he said.

Completely blocking either enzyme can cause side effects such as skin cancer, schizophrenia-like symptoms, and shortened life span, Wong said. Partially inhibiting them, though, cut side effects and helped reduce plaque production, he said.

Using that information, the researchers looked at what would happen if both enzymes were simultaneously limited without being blocked entirely. The scientists found the combination more effectively reduced plaque buildup without the side effects in mice.

“It suggests this would be a terrific therapeutic strategy,’’ Wong said.

To model how the drugs might work, the researchers altered mice genetically to carry the Alzheimer’s gene. One group had reductions in both enzymes, one a reduction in gamma-secretase, and one a reduction in beta-secretase. A fourth Alzheimer’s group was left alone, and a fifth group - the control - consisted of normal mice without the gene.

The researchers used a maze set in water to chart how well the different groups were able to remember directions, and found that mice with reductions in both enzymes performed “nearly as well’’ as the control group, while others did poorly, Wong said.