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A hopeful horizon?
OFF THE BEATEN PATH

A biotech startup thinks its idea could cure dementia—but scientists have their doubts

Katherine Ellen Foley
By Katherine Ellen Foley

Health and science reporter

From our Obsession

The Aging Effect

New thinking is required to serve an aging population.

Scientists know a lot about the hallmarks of different types of dementia. Alzheimer’s 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. Parkinson’s 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 wouldn’t work for someone who doesn’t have amyloid buildups in their brain.

But to this day, there are no definitive treatments—or preventive measures—for 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?

That’s the thinking of Michael Fossel, the founder of the Michigan-based biotech startup Telocyte, which is developing treatments for Alzheimer’s. Today (Jan. 14), Fossel published a review article postulating that Alzheimer’s 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 theoretical—it’s a review, so it’s not presenting any original data. It’s a new way of thinking, and a bold proposition. “It’s 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 Alzheimer’s Association. The Alzheimer’s Association is  a nonprofit and publisher of Alzheimer’s and Dementia, the journal in which Fossel’s review article appeared.

But while theories are important, Edelmayer says, “they also need to be tested.” Gene therapies are still relatively new. And there’s 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 Fossel’s systematic theory of dementia, they’ll need a lot of data demonstrating its safety.

Is telomerase worth exploring for dementia?

Telomerase has been a focus of longevity research for years. It’s an enzyme that lengthens telomeres, which are the genetic caps on the end of our chromosomes. Every time cells divide, telomeres shorten—and 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 it’s 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 cell’s DNA. As telomeres shorten with cell replication, cells change the way they carry out other genetic instructions, which can result in shoddy protein production. It’s a process called the telomere positron effect (paywall), and scientists still don’t fully understand it.

Fossel posits that when telomeres shrink in microglial cells, part of the brain’s immune system, other critical parts of their DNA degrade, too—and that genetic damage can result in many different dementias.

Telocyte’s 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, isn’t 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 person’s faulty or missing genetic code. Telocyte’s gene therapy, however, wouldn’t be replacing a gene: It’d 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.

That’s for good reason: Telomerase is active in most forms of cancer. Which is why many scientists fear that inserting a gene that codes for telomerase—like Telocyte’s gene therapy—risks 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 don’t know whether the over-expression of telomerase will increase the risk of cancer.” In the brain, particularly in the glial cells that Fossel’s 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 cancer—but 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 don’t 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 today—and the one Fossel proposes using—should 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.

Are the risks worth it?

Given the risks, there’s disagreement over whether the telomerase approach is worth pursuing. “It’s important and interesting to have an additional hypothesis,” says Diego Forero, a researcher at the School of Health Sciences at the Fundación Universitaria del Área Andina in Colombia. His work, which is independent of Fossel’s, focuses on exposing astrocytes, a type of glial cell in the brain, to telomerase, to see how they’ll react. He’s found that telomerase is involved in other cellular functions, like a cell’s metabolism. In his opinion, it’s too early to say that Fossel’s 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 target—like a cure for dementia—wouldn’t 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. They’re ineligible for most other clinical trials for dementia therapies, which tend to seek out participants who have risk factors of the disease but minimal symptoms—or none at all.

“People have faced terrible disease and said ‘I’m going to take my chances,’” says Arthur Caplan, a bioethicist at New York University’s Langone Medical Center. With vulnerable populations desperate for treatment, peer review from independent scientists becomes even more important. It’s critical that the data and research are conducted by parties that don’t 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 subjects—especially 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, it’s taken its work to Colombia, where the standards for institutional review boards aren’t as high as they are in the US. It’s a tactic informally known as “IRB shopping,” and it raises eyebrows in the research community.

“We’re 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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