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TorreyPines Therapeutics and Massachusetts General Hospital Researchers Identify Gene That May Increase Risk of Late-Onset Alzheimer's Disease

Posted on: Thursday, 24 March 2005, 09:01 CST

SAN DIEGO, March 24 /PRNewswire/ -- Researchers at TorreyPines Therapeutics and MassGeneral Institute for Neurodegenerative Disorders (MIND) have identified a gene variant that may increase the risk of late-onset Alzheimer's disease. Specific changes in the gene, which encodes a protein called ubiquilin-1, appear to be associated with an increased incidence of Alzheimer's disease in two large study samples. The findings were reported in the March 3 issue of the New England Journal of Medicine. The Massachusetts General Hospital (MGH) team of researchers was led by TorreyPines Therapeutics co-founder, Rudolph E. Tanzi, Ph.D., director of the MIND Genetics and Aging Research Unit and senior author of the study. The results of this research could lead to an improved understanding of the Alzheimer's disease mechanism and a target for the development of new, more effective therapeutics, according to Neil Kurtz, M.D., President and CEO of TorreyPines Therapeutics.

"Our scientists have developed a significant expertise in the identification of the genes associated with Alzheimer's disease," Dr. Kurtz said. "Working with Dr. Tanzi, we have uncovered a number of novel genes on Chromosomes 9 and 10, including the gene reported in this paper, and are focused on converting them into viable pharmaceutical targets. We believe that genetic screening assays for these genes could be used to identify subgroups of Alzheimer's disease patients that will respond particularly well to a given treatment. This 'personalized medicine' approach may be the most effective in treating multi-genetic diseases such as Alzheimer's disease."

Mutations that raise the risk of Alzheimer's disease have been found in four genes. Three of these -- involving the amyloid precursor, presenilin 1 and presenilin 2 proteins -- cause rare, inherited, early-onset forms of the devastating disorder. The only genetic variation associated with the more common late-onset form is ApoE4, which increases risk but does not directly cause the disease. Researchers expect that several additional genes that affect the risk of developing Alzheimer's disease will be found.

In 2003, the MGH research team published results of a full-genome screen of Alzheimer's disease patients and their affected siblings in a sample of 437 families compiled by the National Institute of Mental Health (NIMH). That study identified several potential chromosome "hotspots" that could be associated with increased risk, one of the strongest on chromosome 9. Since the gene for ubiquilin-1, which is known to interact with the presenilins, resides in the same area of chromosome 9, the researchers chose to test it as a candidate gene.

For the current study the investigators analyzed several sequence variations in ubiquilin-1 and two other candidate genes located nearby on chromosome 9. Using a technique called family-based genetic association analysis, the team of scientists evaluated 19 sequence changes in these three genes, searching for alterations more likely to appear in patients with Alzheimer's disease. After first screening families from the same NIMH study the group examined in the 2003 full-genome screen, they retested potential associations in a separate group of 217 sibling pairs. The results confirmed that particular changes in the ubiquilin-1 gene sequence occurred more frequently in individuals with Alzheimer's disease than in their unaffected siblings.

"The same variants of this gene conferred increased risk for Alzheimer's in both of these large study groups," Dr. Tanzi said. "It was very encouraging to have the results confirmed in so many families."

The research team then studied brain tissue from Alzheimer's patients and controls to see if the identified gene variants actually change the production of ubiquilin-1. In both groups, the same gene variants that increased the risk of Alzheimer's also led to increased production of a shorter form of ubiquilin-1, an overproduction that was even more pronounced in the patients.

"Now we need to figure out what's wrong with too much ubiquilin-1 and with this different form," says Dr. Tanzi. "We need to look at how this variant interacts with the presenilins and what effect that may have on the production of A-beta, the protein that accumulates in the amyloid plaques found in the brains of Alzheimer's patients."

The researchers estimate that the increased risk accompanying these ubiquilin-1 gene variants is nearly half that conferred by ApoE4. They and other research groups expect that 4 to 7 additional gene variants may be found that confer similar levels of risk.

About TorreyPines Therapeutics

TorreyPines Therapeutics, formerly Neurogenetics Inc., is a biopharmaceutical company that discovers and develops breakthrough small molecule drugs to treat diseases and disorders of the central nervous system. Led by an accomplished management team, the company is leveraging novel drug targets and technologies to deliver new therapies for migraine, neuropathic pain and neurodegenerative disorders such as Alzheimer's disease. Its breakthrough therapies are intended to offer significant advantages over current therapies. Further information is available at http://www.torreypinestherapeutics.com/.

TorreyPines Therapeutics, Inc.

CONTACT: Craig Johnson of TorreyPines Therapeutics, Inc.,+1-858-623-5665 ext. 158, cjohnson@torreypinestherapeutics.com; or Kathy W.Sweeney of Mentus, +1-858-455-5500 ext. 230, kwitz@mentus.com, for TorreyPinesTherapeutics, Inc.

Web site: http://www.torreypinestherapeutics.com/

Source: PRNewswire

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