Down syndrome may hold key to new Alzheimer's treatments

CHICAGO Tue Sep 25, 2012 3:52pm EDT

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CHICAGO (Reuters) - In a new lead on Alzheimer's research, Johnson & Johnson is bankrolling a three-year pilot study of people with Down syndrome to identify the early changes that herald dementia, which afflicts up to 75 percent of adults with the condition.

The aim is to generate support for a much bigger, public-private partnership funded by drugmakers, advocates and government agencies that will study at least 1,000 people with Down syndrome, tracking them from an early age and eventually testing treatments to keep dementia from developing.

"The study we're proposing would provide insight into treating Alzheimer's, but it might help individuals with Down syndrome as well," said Dr. Husseini Manji, J&J's global head of neuroscience drug development.

Experts in Down syndrome and Alzheimer's who gathered in Chicago for a workshop on the idea at the Alzheimer's Association offices this month say it may offer the best scientific model yet for testing drugs to prevent the degenerative brain disease.

The industry has been repeatedly stung by the failure of experimental Alzheimer's treatments, including recent trials of the J&J and Pfizer Inc therapy bapineuzumab. As a result, companies and researchers are looking for ways to test Alzheimer's drugs earlier, before people's brains become too damaged to benefit.

Studies are already planned to enroll people who carry genetic mutations that ensure they will develop Alzheimer's at an early age. One trial backed by the U.S. Department of Health & Human Services will test a drug from Roche Holding AG's Genentech unit called crenezumab in an extended family from Colombia who carry a mutation that causes them to develop Alzheimer's in their 30s.

Only a few hundred families in the world carry these genes, and there is some worry that drugs tested in people with genetic mutations that cause early-onset Alzheimer's may work differently in people who develop the more common late-onset Alzheimer's, which develops after age 65.

AN IMPORTANT DIFFERENCE

The dementia that develops in people with Down syndrome may bear a stronger resemblance to the disease in the broader population because it differs from other forms of early-onset Alzheimer's, researchers say.

People with Down syndrome inherit a third copy of chromosome 21, giving them an extra helping of a gene that makes amyloid precursor protein, or APP, which is linked with the development of plaques in the brains of Alzheimer's patients.

Most early-onset Alzheimer's is caused by mutations in the APP gene or in one of two genes known as presenilin 1 or presenilin 2. People with Down syndrome appear to develop dementia because of their extra copy of an otherwise normal APP gene.

"There is a possibility that the Down syndrome population mimics (late-onset) Alzheimer's disease a little more closely," said Manji, co-author of a commentary this month in Nature Reviews Drug Discovery that laid out plans for the study.

Dementia starts much earlier in people with Down syndrome, who develop brain plaques and tangles by age 30 and signs of dementia by age 40.

The number of potential Down syndrome patients exceeds those with the genetic mutation. There are some 400,000 people in the United States and 6 million people worldwide with Down syndrome.

"These diseases almost certainly have common features," said Dr. William Mobley of the Down Syndrome Center for Research and Treatment at the University of California, San Diego.

While all of the similarities are not yet clear, studies in mice with Down syndrome show that just eliminating just the extra copy of the gene for APP can keep brain cells from dying, he said.

Mobley's center will run the 12-patient pilot study, which aims to lay the foundation for the larger project, dubbed the Down Syndrome Biomarker Initiative.

The larger trial would be patterned after two successful studies: the Alzheimer's Disease Neuroimaging Initiative, a public-private partnership that helped identify biomarkers linked with Alzheimer's, and a breast cancer trial known as I-SPY that pioneered adaptive trial design, in which researchers use biomarkers to match the right drug to the right patient.

What is not yet known is how many parents of people with Down syndrome would be willing to sign up their adult children for such trials. Michelle Whitten of the Global Down Syndrome Foundation thinks many will be.

Whitten, the mother of a 9-year-old with Down syndrome, says the lifespan of people with the condition has increased from 28 years in the 1980s to 60 years today because of better treatment. That means many parents who fought to give their children a good education and a worthwhile job now frequently face their decline into dementia.

"We just want it solved," Whitten said.

Dr. Michael Krams, who heads the neurology franchise at J&J, said the challenge is to develop drugs that offer lots of potential benefit with little risk to patients.

That may rule out the company's drug bapineuzumab, which was shown to cause brain-swelling known as vasogenic edema in several patients.

Krams said one promising approach would be a beta-secretase, or BACE, inhibitor, a drug designed to keep the enzyme beta-secretase from chopping up APP into bits that produce beta amyloid, which forms brain plaques in Alzheimer's patients.

A recent study in the journal Nature hinted that inhibiting beta-secretase might work. A team at deCODE Genetics in Reykjavik discovered a rare mutation in the APP gene that protects against Alzheimer's, and it works by interfering with beta-secretase. Drugmakers who are already developing BACE inhibitors include Eli Lilly and Co, Roche, and Merck & Co.

Krams declined to say if J&J also has a BACE drug, but he said testing such drugs in patients with late-onset Alzheimer's would require very large trials.

"At least conceptually, doing this in a Down's population might be much more efficient."

(The story fixes spelling throughout of Michael Krams' last name.)

(Editing by Michele Gershberg and Prudence Crowther)

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