A gene bath in the brain to prevent Alzheimer's disease

In France alone, Alzheimer's disease affects one million people, mobilises two million carers and costs the community €20 billion. But there is no cure. And yet, scientists regularly announce discoveries and experiments that quickly prove to be ineffective. The dream of proposing a treatment that prevents the development of Alzheimer's seems to be an impossible dream. But this time, we can start believing it. American doctors have taken a different path from those currently being explored: that of gene therapy. An original and audacious approach whose initial results seem very promising.

 

Fe have a dream: imagine that Alzheimer's disease can be treated as a common ailment. Instead of worrying about slowly losing your memory, in middle age you would be given a treatment designed to prevent this neurological nightmare from developing. Unfortunately, this is only a dream because Alzheimer's disease is, for now, impossible to beat. Yet doctors are not shying away from the efforts and means to find the miracle solution. But the series of drugs that promised great promise is long: none have been able to prove their effectiveness and pass the barrier of clinical trials.

 

This degenerative disease, which affects tens of millions of people around the world, has blocked researchers for years. Yet we know pretty well how this disease works. It develops when two proteins - A-beta and tau - accumulate in the brain. The A-beta accumulates outside the nerve cells, and tau...inside. Decades of studies suggest that theA-beta somehow leads to the accumulation of tau, which in turn causes nerve cell death. According to Marc Diamond, a leading specialist in this disease, neurodegeneration starts with a change in the shape of the protein tauwhich then forms toxic assemblages, or "clumps", in the brain. These assemblies are mobile and appear to transmit pathologies between different groups of neurons causing disease progression. Like the protein tau appears to play a central role in the destruction of brain cells, and because lost neurons cannot be replaced, researchers are working to develop tools to detect early signs of the protein tau toxic. This can happen many years before cognitive symptoms become apparent. But, unfortunately, this work hasn't made it past the labs yet.

 

The discovery of a drug to treat Alzheimer's is a multi-billion dollar question; a jackpot that seems, in the current state of knowledge, very unlikely. So why not change strategy? Why bother looking for a drug? Why not look for a way to prevent the development of Alzheimer's at the earliest possible stage? This is where a medical team from Weill Cornell Medicine in Manhattan, led by Dr. Ronald Crystal, comes in. Their tactic is to avoid the endless debate about the true cause of Alzheimer's disease.  "Some people think it's the amyloid that's responsible; others say it's the tau protein that gets tangled up in the destroyed neurons.. "We don't know," he told the MIT Review. It has therefore adopted a strategy that ignores these debates and focuses solely on the genetic point of view.

 

Dr. Crystal's idea is to build on a twenty-five year old discovery. In the 1990s, researchers at Duke University in the United States went fishing for any proteins they could find attached to amyloid plaques. They identified apolipoprotein E, a protein encoded by the APOE. By sequencing this gene in a cohort of patients, they determined that one version of this gene, APOE4, was inexplicably common in people with the disease.

The function of this gene is not yet well understood (it plays a role in the transport of cholesterol and fats) but its status as a risk factor remains formidable. According to Alzheimer AssociationApproximately 65 % of people with Alzheimer's disease have at least one copy of the risk gene. For people born with two high-risk copies, one from each parent, dementia becomes almost certain if they live long enough.

 

What you need to know is that each of us has two copies of this APOE gene: one from our mother, one from our father. This gene exists in three common versions called type 2, type 3 and type 4. Russian genetic roulette will assign you to one of these types. But what we now know is that the APOE type 2 gene determines a low risk of developing Alzheimer's disease, type 3 determines a medium risk, and type 4 is the big jackpot, determines the maximum risk. The risk is such that doctors are refusing to test their patients for the ALOE 4 gene because knowing this would be of no use except to cause serious concern because there is no cure and there is simply nothing that can be done.

 

The doctors on Dr. Crystal's team chose not to submit to this fatality. The idea they developed is simple: if you have type 4 genes in your brain, why not inject high doses of type 2 genes - the least risky - to radically change the proportions and make type 2 genes the dominant genes?

The goal of doctors is to slow down Alzheimer's disease in people who already have it, and eventually lead to a way to prevent the disease.

 

L’clinical studyThe new Gene Therapy Initiative, led by Ronald Crystal at Weill Cornell Medicine in Manhattan, is a new tactic in the fight against dementia as well as a new direction for gene therapy. Until now, this type of therapy has involved targeted delivery of RNA-directed viruses to the cells of a person with a rare disease such as hemophilia. But for Alzheimer's, the causes are multifactorial and this type of treatment has proved unsuitable. On the other hand, it is now known that people who inherit a type 4 gene associated with a type 2 gene have a medium or low risk of developing the disease. This suggests that the protective version of the gene compensates for the effects of the gene at risk.

That's exactly the effect Weill Cornell's doctors will try to copy. The centre is now looking for people with two copies of the high-risk gene who already have memory loss, or even a proven diagnosis of Alzheimer's disease. Starting in about a month, says Crystal, the first volunteers will receive an infusion of billions of viruses carrying gene 2 into their spinal cords.

 

Based on tests on monkeys, Dr. Crystal expects viruses to spread the gene for good luck to patients' brain cells. Mice treated in the same way, depending on their centres, accumulated less amyloid in their brains. The strategy, Crystal repeats, does not depend on knowing everything there is to know about the real causes of the disease. « What attracts us to Alzheimer's disease is that the genetic epidemiology is so obvious " he says. " So the strategy is simple: can we bathe the brain in type 2 APOE? We have the infrastructure to do it, so we thought, why not? By doing so, we get around the problem of the mechanism of the disease. ".

 

The New York study is preliminary. Crystal says her team needs to determine if the added gene works at a detectable level. Doctors will take cerebrospinal fluid from patients and see if it contains the intended mixture of proteins - the intended type 4, but now with an equal or greater amount of type 2 mixed in.

 

This first experiment will not change the lives of the patients who are the subject of this first test. In fact, when people start forgetting names and no longer know where their car keys are, it is because the disease process has already started a long time ago, at least ten years ago. At a certain stage, any medical action is useless; it is necessary to act earlier.

 

That being said, Dr. Crystal's approach seems sufficiently interesting and promising that the Alzheimer Foundation, which is involved in drug discovery, has decided to fund this new research to the tune of $3 million. « We don't know what's going to happen yet. "says Nick McKeehan, Deputy Director of the Foundation. « But it's a stepping stone. We may have to treat people sooner. That's opening the door to that kind of therapy. "

Ultimately, scientists hope that middle-aged people with genes at risk may undergo one-time genetic adjustments. Even a small reduction in the rate at which brain changes occur could make a big difference over time.

 

The doctors are optimistic but cautious. According to Susan Hahn, a genetic counsellor interviewed by the MIT review, " Certainly, Alzheimer's disease is the most dreaded disease in the world, because it is horrible to lose your mind. People would rather have cancer or a heart attack... ». But she immediately adds " people shouldn't have their APOE gene levels tested without a good reason. You need to be prepared for what you're going to hear, because it's definitive. You can't change your genes; however, with this research, you will somehow be able to do so. ".

 

 

 

Source: MIT Technology Review