Could a gene therapy cure dementia? – Quartz

Posted: January 15, 2020 at 1:46 pm

From our Obsession

New thinking is required to serve an aging population.

Scientists know a lot about the hallmarks of different types of dementia. Alzheimers disease is characterized by buildups of amyloid and tau proteins. Vascular dementia is the result of gnarled and broken blood vessels that normally supply oxygen to the brain. Parkinsons disease and other Lewy Body dementias are caused by misshapen alpha-synuclein proteins in the brain.

Conventional wisdom has it that each of these dementias needs its own treatment. An anti-amyloid drug probably wouldnt work for someone who doesnt have amyloid buildups in their brain.

But to this day, there are no definitive treatmentsor preventive measuresfor any of the dozens of dementias out there. Which has led some researchers to take a more systematic approach: What if there were a single mechanism in the brain that, when faulty, leads to all kinds of dementias? And what if this mechanism, like a switch, could be flipped off?

Thats the thinking of Michael Fossel, the founder of the Michigan-based biotech startup Telocyte, which is developing treatments for Alzheimers. Today (Jan. 14), Fossel published a review articlepostulating that Alzheimers and other dementias are caused by a failing of a workhorse class of brain cells called glia. He also proposes that he and his colleagues at Telocyte, founded in 2015, have a solution: a gene therapy that could target these cells to keep dementia at bay.

The paper is theoreticalits a review, so its not presenting any original data. Its a new way of thinking, and a bold proposition. Its encouraging to see individuals like Dr. Fossel pulling together research and trying to come up with new theories, says Rebecca Edelmayer, the director of scientific engagement at the Alzheimers Association. The Alzheimers Association is a nonprofit and publisher of Alzheimers and Dementia, the journal in which Fossels review article appeared.

But while theories are important, Edelmayer says, they also need to be tested. Gene therapies are still relatively new. And theres reason to wonder about the safety of the gene the therapy would introduce: one that codes for the enzyme telomerase. Before scientists can even begin to test Fossels systematic theory of dementia, theyll need a lot of data demonstrating its safety.

Telomerase has been a focus of longevity research for years. Its an enzyme that lengthens telomeres, which are the genetic caps on the end of our chromosomes. Every time cells divide, telomeres shortenand when telomeres have been sufficiently shaved away, cells enter a state called senescence and stop dividing. Then, they self-destruct.

Shorter telomeres have been correlated with a whole host of age-related health issues: cancer, diabetes, and even forms of dementia. But its not the telomeres themselves that cause these issues, Fossel suggests. As my telomeres shorten, there are a lot of other things going on, too, he says.

The relative length of telomeres, we know, sends a signal to the rest of the cells DNA. As telomeres shorten with cell replication, cells change the way they carry out other genetic instructions, which can result in shoddy protein production. Its a process called the telomere positron effect (paywall), and scientists still dont fully understand it.

Fossel posits that when telomeres shrink in microglial cells, part of the brains immune system, other critical parts of their DNA degrade, tooand that genetic damage can result in many different dementias.

Telocytes gene therapy would aim to rebuild those glial telomeres. That would involve sending an active copy of the telomerase gene, TERT, into the cerebrospinal fluid, carried by a virus. The virus, which should be otherwise benign, isnt great at getting genetic material into specific cells: in mouse models, about 5% of the total therapy winds up in neurons, to no lasting effect, and about 1% winds up in microglial cells, Fossel says. But even with the TERT gene just floating around in the glial cell for a few weeks or months, it might be enough for telomerase to lengthen those end caps and trick the cell into expressing genes like it did in its younger days.

Usually, gene therapies work by introducing new genetic material that replaces a persons faulty or missing genetic code. Telocytes gene therapy, however, wouldnt be replacing a gene: Itd just be giving glial cells another copy of one they already have. All of our cells have the TERT gene embedded in their chromosomes. But the vast majority of cells (save for red blood cells, sperm or egg cells, and cells along parts of the digestive tract) have the gene switched permanently off.

Thats for good reason: Telomerase is active in most forms of cancer. Which is why many scientists fear that inserting a gene that codes for telomeraselike Telocytes gene therapyrisks causing cancer

My main concern is its safety, says Jue Lin, molecular biologist at the University of California San Francisco whose work focuses on studying telomere length and stress levels over time. We dont know whether the over-expression of telomerase will increase the risk of cancer. In the brain, particularly in the glial cells that Fossels proposed gene therapy would target, the cancer in question would likely be glioblastoma, a ravenously growing brain tumor.

Mouse models using telomerase gene therapy in the brain have been promising, with no notable incidence of cancerbut those experiments are imperfect. Mice express telomerase differently than humans do, Lin explains: They have a lot more telomerase, in more tissues than humans. Mice also dont live as long as we do, and cancer takes a long time to develop, Lin says.

And gene therapies carry the risk of a dangerous immune reaction to the virus carrying the therapeutic gene. The viruses used in gene therapy todayand the one Fossel proposes usingshould be safer than the ones used in the early days of gene therapy. Adeno-associated virus, or AAV for short, should elicit only the tiniest of immune responses. But scientists have recently voiced concerns about the long-term safety of gene therapies using AAV.

Given the risks, theres disagreement over whether the telomerase approach is worth pursuing. Its important and interesting to have an additional hypothesis, says Diego Forero, a researcher at the School of Health Sciences at the Fundacin Universitaria del rea Andina in Colombia. His work, which is independent of Fossels, focuses on exposing astrocytes, a type of glial cell in the brain, to telomerase, to see how theyll react. Hes found that telomerase is involved in other cellular functions, like a cells metabolism. In his opinion, its too early to say that Fossels theory should be tested.

Rather than focusing on the potential therapeutic application of telomerase in brain cells, Forero is interested in more basic, exploratory research. He thinks that applying it to a specific targetlike a cure for dementiawouldnt tell scientists enough about all the ways telomerase could affect brain cells.

Those calls for prudence can be frustrating for dementia patients facing a dearth of options. Even with no immediate plans to conduct clinical trials, Fossel says he has already had some 200 people with mild to moderate dementia reach out to him as willing participants. Theyre ineligible for most other clinical trials for dementia therapies, which tend to seek out participants who have risk factors of the disease but minimal symptomsor none at all.

People have faced terrible disease and said Im going to take my chances, says Arthur Caplan, a bioethicist at New York Universitys Langone Medical Center. With vulnerable populations desperate for treatment, peer review from independent scientists becomes even more important. Its critical that the data and research are conducted by parties that dont have a vested financial interest in a certain outcome.

These studies also need to have strong institutional review boards, Caplan says. These boards are required any time researchers are conducting experiments with human subjectsespecially when the risks are so high.

Libella Gene Therapeutics, a Kansas-based biotech startup, is beginning a clinical trial for a telomerase gene therapy to treat broad aging this year. However, its taken its work to Colombia, where the standards for institutional review boards arent as high as they are in the US. Its a tactic informally known as IRB shopping, and it raises eyebrows in the research community.

Were always open to new ideas and novel ways [to treat dementia, Edelmayer says. We have to leave no stone unturned. But, she continued, one of the biggest things we want to see is not just theories. We want to see them tested.

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Could a gene therapy cure dementia? - Quartz

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