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Tuesday, Feb. 19, 2002
Gene study sheds light on Alzheimer's disease
By GARY TEGLER
OSAKA -- Researchers at Osaka University have announced a breakthrough in determining the cause of Alzheimer's disease, raising hopes for improvements in the treatment of the currently incurable ailment that reportedly affects 1 million Japanese aged over 65.
Using sophisticated scanners, seven medical researchers headed by Masaya Tohyama studied mutations in three genes known to be related to the cause of Alzheimer's. Under hypoxic conditions -- a lack of oxygen due to an accumulation of hyper-free radicals, a mutation in a gene called PS2 is caused when the protein HMG-I binds itself to the end of an exon, a gene fragment that allows DNA to be read, within the PS2 gene, resulting in an aberrant splice between exons 4 and 6.
The shortening of the exon sequence generates a PS2-variant gene. This mutation then affects other agents resulting in a buildup of abnormal or unfolded proteins. The cell, or cells, eventually die and lead to a loss of memory and greatly impaired motor skills, known clinically as dementia.
"Although several genetic diseases are known to be caused by mutations, the study of the factors that modulate the splicing of normal genes has not been well documented," said Taiichi Katayama, a research associate at Osaka University and spokesman for the project. Based on the discovery of aberrant splicing in the PS2 gene, the group was then able to experiment with various countermeasures.
"We designed a decoy RNA sequence that affected the relevant cells and stimulated these cells under hypoxic conditions," Katayama said. "We found that the number of PS2-variant genes was decreased and that the buildup of unfolded proteins was thus inhibited."
The group's findings will be published later this year and plans are going ahead for clinical experiments to be conducted in the laboratories of Tokyo-based Taisho Pharmaceuticals Co. to try to come up with an effective medicine.
The importance of such discoveries is significant in a country like Japan, where government statistics show that by 2050, over a third of the population will be 65 or over. This, coupled with an estimated drop in the population of some 27 million between 2006 and 2050, means the scramble is on to find a cure for Alzheimer's.
However, there are several causes of the disease, ranging from genetic mutations to vascular constriction.
Katayama explained that the group's discovery is related to patients affected with the "sporadic" form of the illness, a slow buildup of beta-amyloid in the brain, as opposed to the "familial" strain, which, although pathologically the same, is the result of a certain inheritance pattern and affects less than 10 percent of sufferers. Cures are still a long way off, according to Toshiki Mizuno, a professor at Kyoto Prefectural Medical University's Department of Neurology and Gerontology.
"Results from this research will not be seen in the near future, but perhaps in 10 years," Mizuno said. "It will be a large, ongoing project to make an effective drug and even then there are other causes that will have to be addressed. But in Japan, dementia is the most serious social and medical problem, and this research is absolutely necessary."
The drugs, when and if they arrive, will also be expensive, according to Katayama. The time and cost to universities and pharmaceutical companies will mean high prices for medicines, and large profits for the organizations involved.
Firms that include Eisai Co. and Yamanouchi Pharmaceutical Co., both based in Tokyo, in conjunction with European and U.S. companies, have already begun marketing drugs to slow the progress of Alzheimer's in its early stages.
In the case of Eisai, sales of these and other neurological drugs will account for nearly a third of the company's profits this fiscal year, according to officials of the firm.
Further spurring the race to find treatments and cures is the high cost borne by families and governments for treating Alzheimer's patients.
Though statistics are hard to come by in Japan, the Alzheimer's Association in the United States estimates that the lifetime cost per patient for treatment is around $174,000, while businesses incur just over $3 billion annually in related costs.