The field of Alzheimer's research is filled with disappointment. Last week, another drug failed its Phase 3 clinical trial and continued its 15-year defeat as a truly new Alzheimer's treatment was approved by the Food and Drug Administration.
But a team of scientists this week says there was early evidence in mice that an existing class of medications can attack Alzheimer's disease and similar diseases from a different angle than earlier failures.
The question of the causes Alzheimer's has no easy answers. We know that two proteins that are naturally produced in the brain – beta-amyloid and tau – are inextricably linked to the neurological disorder. In someone with full-blown Alzheimer's, abnormal clots of both proteins, called plaques or tangles, form and scatter – the brain (plaques are mostly in the space between nerve cells, while tangles tend to form in nerve cells). However, we do not know whether one, both, or none of these structures is primarily responsible for the progressive, ultimately fatal brain damage in Alzheimer's disease.
The most prevalent theory of the disorder is that beta-amyloid is the principle of the bad guy, in part plaques seem to emerge from tau complications. Therefore, scientists and drug companies have set their hopes on drugs that can break these plaques or prevent their accumulation in the brain. However, a study after hearing these anti-amyloid drugs did not significantly improve people's symptoms or slow the progression of the disease. Often the failure of the drug becomes clear only at the end of the test phase in humans.
This drug has a different goal than most of these high-profile studies. But maybe not even the tau protein is the ultimate goal.
The recent failed studies with aducanumab, which were prematurely terminated by Biogen and the Japanese pharmaceutical Eisai last week, were particularly daunting. Aducanumab appeared to be better at eliminating plaques than previous medications and was tested on patients with the earliest clinical stages of Alzheimer's – two factors that should have increased the chances of success. These failures have again led to calls of the scientific community to completely rethink or even shift the focus and resources of the amyloid hypothesis of Alzheimer's disease as it is called.
The researchers behind this latest study published on Wednesday in Science Translational Medicine For years, he has pursued one of these alternative approaches.
Her research, led by Kenneth Kosik, a neurologist at the University of California, Santa Barbara, focused on tau as the main driver of Alzheimer's and not of amyloid. While tau complications later emerge in the development of the disease, some research has shown that the spread of abnormal tau correlates better with the apparent progression of the disease than amyloid (in contrast, plaques can be found in the brain of people without visible dementia). And we already know that there are other neurological disorders, such as frontotemporal dementia, which are almost exclusively caused by tau-tangles. Many people with frontotemporal dementia have also inherited genetic mutations that involve the production of tau, greatly increasing the risk of complications.
"In Alzheimer's disease, you can discuss the problem, but there is no question about these cases," Kosik told Gizmodo.
Kosik and his team discovered a discovery when investigating these tau mutations. Having found a previously unrecognized regulatory pathway in cells that can trigger the breakdown of healthy dew, this pathway appears to work through a protein called Rhes, which belongs to a larger family of proteins called Ras, which itself becomes an enzyme Fortunately, there are already drugs that inhibit farnesyltransferase.
These farnesyltransferase inhibitors (FTIs) were originally developed as anticancer drugs because mutant Ras protein is also common in tumors and some even achieve human trials they were considered safe enough for the humans, they were not yet as Krebsthera pien. However, Kosik and his team hypothesized that FTIs could be reused to treat tau-related brain diseases, including Alzheimer's disease.
So far, their work in mice and human neurons (grown from the stem cells of people with genetic characteristics) Linked Frontotemporal Dementia) seems to confirm their educated presumption. When giving FTI, called lonafarnib, to mice bred with a form of frontotemporal dementia, the progression of dementia symptoms slowed noticeably. The brains of the treated mice also had less abnormal dew and inflammation than control mice. And in a petri dish, the damaged human neurons were better able to produce healthy dew when exposed to lonafarnib.
Of course, this would hardly be the first time that animal studies have given a glimmer of hope for a possible new dementia treatment. However, Kosik pointed out that one of the benefits of lonafarnib compared to other experimental drugs is that it has been well studied.
"This is a drug that is safe for humans. That means it can be reused for people with illnesses caused by complications, "said Kosik." When tested on humans, they should be used in people with a very mild illness or even before the onset of symptoms become. And I think that this must be one of the next steps.
Despite this optimism, the Kosik team faced several hurdles in further research into the drug. Lonafarnib is also being studied for use in the treatment of rare progeria with rapid aging. Promising clinical trials are expected to pave the way for FDA approval. However, Kosik says drug makers, Eiger BioPharmaceuticals, have refused to provide their team with more medicines for further human research. If Lonafarnib can no longer be used, his team would have to find other FTI candidates.
Apart from logistics, Kosik is aware of the recent grim developments in the search for a new treatment for neurological conditions such as Alzheimer's. But he hopes that he and others have learned from the mistakes of the field in their own research and become.
"This drug has a different goal than most of these high-profile studies. But maybe even the tau protein is not the right target. Maybe we need to look at other aspects of the disease, like inflammation, "he said.
Despite his own theory, Kosik does not support the idea of turning away from amyloid, but to be smarter about how we do Alzheimer's research in general and pursue multiple potential treatment options that are strongly supported by basic research.
"The lessons we should learn from these studies are not to turn off a whole aspect of disease research, but to rethink how we approach these clinical trials," Kosik said. "I am also a clinician and I understand that if you have a patient who asks you for something all that could help, the temptation is very strong to try something. But so many of these exams are Ave Maria. What we really need more than anything else is a deeper understanding of the cell biology underlying this disease. "