Gene Therapy for Alzheimer’s Disease Prevention – Credence Turbine

No one knows for sure what causes Alzheimers disease. But one fact about the condition has acquired an almost irrefutable status. Depending on what variants of the APOE gene you inherit, the risk of brain disease can be half the average or more than 12 times as high.Often referred to as the forgetting gene, APOE comes in three popular forms, 2, 3, and 4. Type 2 decreases the risk of an individual, 3 is normal, and 4 increases the threat dramatically. The risk is so high that doctors would stop checking patients for APOE because a bad outcome may be upsetting, and theres nothing to do about it. There is no cure, and you cant change your genes, either.

Well, you cant today. But doctors in New York City say that beginning in May, they will start testing a novel gene therapy in which people with the unluckiest APOE genes will be given a huge dose to their brain of the low-risk version.In people who already have Alzheimers, if that slows the brain-wasting illness, it could eventually lead to a way of preventing the disease. The clinical trial, conducted at Weill Cornell Medicine in Manhattan by Ronald Crystal, is a novel tactic against dementia as well as a new gene therapy twist.

Most gene replacement efforts, which rely on viruses to carry DNA instructions into a person s cells, aim to fix rare diseases such as haemophilia by replacing a single malfunctioning gene.But there are no singular causes of common diseases, so gene therapy has never seemed so promising. A trade group, the Alliance for Regenerative Medicine, says it knows of no gene therapies currently being tested for Alzheimers disease patients.

Going into human clinical trials seems like a long shot, but there is a desperate need for any treatment, says Kiran Musunuru, a professor at the medical school of the University of Pennsylvania. Musunuru, who studies genetic treatments for heart disease, says the New York experiment represents a new category of gene therapy in which the goal is not to cure, but to reduce healthy peoples risk of future illnesses.

Crystal says his plan also sidesteps the debate about the real cause of Alzheimers disease, a multi-billion dollar roulette wheel where drug companies and patients continue to lose. In January, Roche launched two major antibody studies aimed at clearing up the characteristic plaques of a protein called beta-amyloid, the latest blow to the theory that the fundamental cause of Alzheimers is these plaques around neurons.

Crystal says, There are those in the field who strongly believe that amyloid does it, while others believe its another protein called tau, tangles of which are found in dying neurons. The answer is probably that its very complex, he says. The approach we have taken is to ignore all that and, from a genetic point of view, think about it.

Crystal s team is relying on a 25-year-old discovery in doing so. Duke University researchers went fishing for any proteins they could find attached to amyloid plaques in the 1990s. They identified the protein encoded by the APOE gene, apolipoprotein-e. They determined that one version, APOE4, was inexplicably common in those suffering from the disease by sequencing the gene in 121 patients.

The function of the gene is still not fully understood (it plays a role in transporting fats and cholesterol), but its status as a risk factor remains frightening. Roughly 65 percent of people with Alzheimers have at least one copy of the risky gene, according to the Alzheimers Association. Dementia becomes close to a sure thing for individuals born with two high-risk copies, one from each parent, if they live long enough.

Some individuals, though, inherit one 4 and one 2, the gene s lowest-risk version. These people are closer to the average risk, suggesting that the genes protective version offsets the risky one.This is the effect that the doctors at Weill Cornell will attempt to copy. The centre is now looking for individuals with two high-risk gene copies who already have memory loss, or even an Alzheimers diagnosis. Crystal says that starting in about a month, the first volunteers will receive a billion viruses carrying the 2 gene infusion into their spinal cords.

Crystal expects the viruses to spread the lucky gene to cells throughout the brains of the patients, based on tests in monkeys. Mice treated in the same way, his centre found, in their brains, accumulated less amyloid.The approach, Crystal says, does not depend on knowing all about what really causes the disease. What attracts us to Alzheimers is that it is so obvious from genetic epidemiology, he says. So the strategy is, can the brain be bathed in E2? Weve got the infrastructure to do it, so we were thinking, why not? The problem of the mechanism of the disease gets around it.

The concept is rational, adds Crystal. Another thing is whether it works within a human being.The study in New York is preliminary. Crystal states that his team needs to determine whether the added gene even works at a detectable level. Doctors will draw the patients spinal fluid and see if it contains the expected protein mix-the expected type 4, but now mixed in with an equal or greater amount of 2.

By the time people begin to forget names and where the car keys are, its a result of brain changes that started a decade earlier. That means that patients who are participating in the trial cant expect much. For them, its probably too late.Even so, Crystal is being given $3 million by the Alzheimers Drug Discovery Foundation to pay for the study, its largest grant to date. We dont know whats going to happen yet, says Nick McKeehan, the foundations assistant director. Its a stepping stone, though. Perhaps well need people to be treated earlier. It opens the door to this kind of therapy.

The hope is that middle-aged individuals with risky genes may eventually undergo one-time genetic tune-ups. Over time, even a small decrease in the pace at which brain changes occur could make a real difference.Alzheimers is the worlds most feared disease, because its horrifying to lose your mind. Susan Hahn, a genetic counsellor who doesnt think people should get their APOE gene tested for good reasons, says people would prefer to have cancer or a heart attack. Because its permanent, you have to be prepared for what you are going to hear. You cant change your genes, although you can perhaps do it with this study.

Source: MIT Technology Review

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Gene Therapy for Alzheimer's Disease Prevention - Credence Turbine