In a bold attempt to halt the progression of some cases of Alzheimer’s disease, a group of researchers are trying something new: injecting a protective gene into patients’ brains.
The trial only involved five patients with a particular genetic risk for Alzheimer’s disease. They received a very low dose of gene therapy – a safety test, which the treatment passed. But preliminary results, announced Friday at the Clinical Trials in Alzheimer’s Disease conference, showed that proteins from the added gene appeared in the patients’ cerebrospinal fluid and that levels in the brain of two markers of Alzheimer’s disease, tau and amyloid, fell. These results were promising enough to advance the clinical trial into its next phase.
Five more patients are being treated at a higher dose, and the work, initially funded by the nonprofit Alzheimer’s Drug Discovery Foundation, is supported by Lexeo Therapeutics, a start-up company founded by Dr. Ronald Crystal, which is also chairman of the department of genetic medicine at Weill Cornell Medicine in New York. The hope is for a stronger response, eventually leading to a treatment that could slow the disease in which it started or, even better, protect those at high risk who have no symptoms.
Experts not involved in the trial are fascinated.
“It’s a very provocative and very intriguing approach,” said Dr. Eliezer Masliah, director of the division of neuroscience at the National Institute on Aging.
The study participants are among the roughly 2% of people who have inherited a pair of copies of a gene, APOE4, that significantly increases their risk of Alzheimer’s disease. For the study subjects, the first symptoms of Alzheimer’s disease had already appeared – their genetic risk had played out and they had few options. There is no treatment specifically directed at APOE4-induced Alzheimer’s disease, nor is there one on the near horizon.
“We’ve known about this risk factor for almost 30 years now,” said Dr. Howard Fillit, co-founder and scientific director of the Alzheimer’s Drug Discovery Foundation. His foundation and other funders supported efforts to correct the effects of APOE4 or treat it with drugs, but to no avail.
With genetic tests like 23andMe readily available, more and more people are learning that they have two copies of APOE4. For some, like 39-year-old “Thor” star Chris Hemsworth, knowledge is life-changing. By an unlikely coincidence, he underwent the genetic test as part of a documentary he was making about life extension. When he learned of the result, he decided to take a break from his acting career.
It’s unclear exactly how APOE4 makes Alzheimer’s disease more likely or why some people with two copies of the variant never get the disease.
What is known is that APOE4 is one of three genetic variants that affect a person’s chances of having Alzheimer’s disease. The others are APOE3 and APOE2. Each person inherits two variants of the APOE gene, and the combination determines the risk.
Compared to the most common variant, APOE3, having at least one copy of the APOE4 variant increases the risk, and having an APOE2 variant decreases the risk.
But estimating the lifetime risk conferred by these variants is tricky. According to Dr. Deborah L. Blacker, a geriatric psychiatrist and epidemiologist at Massachusetts General Hospital, the best data indicates that the lifetime risk of developing Alzheimer’s disease for people with two APOE4 genes is 30-55%. The lifetime risk in people with one APOE4 gene and one APOE2 gene has not been directly estimated but appears to be around 20%, Dr Blacker said.
This leads to the idea that if gene therapy floods the brain with APOE2, converting the brain midpoint of a person with two APOE4 variants to one that resembles that of a person with one APOE4 and one APOE2, it could eventually halve the risk of Alzheimer’s.
Recruitment to try the technique has been slow, said Dr. Sam Gandy, a professor of Alzheimer’s disease research at Mount Sinai in New York, who was one of the study’s researchers. Not everyone wants to sign up to have a virus carrying a gene injected into their brain.
But, he said, Alzheimer’s disease is so terrible and people with two copies of APOE4 are at such risk that “desperate times call for desperate measures.”
The idea of APOE2 gene therapy originated 25 years ago, when gene therapy and the discovery of APOE variants were still in their infancy. Three researchers who were then at Rockefeller University – Dr. Michael G. Kaplitt, now professor of neurological surgery at Weill Cornell Medicine, Dr. Gandy and Dr. Paul Greengard – published an essay suggesting so.
But, said Dr Kaplitt, the technologies at the time were not enough, and researchers moved on to other projects.
The idea, he said, “languished”.
Now, thanks to advances that make this possible, researchers are able to use a harmless virus, AAV, to transport copies of the APOE2 gene to the brain. The virus and its cargo of genes reach the brain after being injected directly into the cerebrospinal fluid.
Dr Kaplitt, who is leading the trial, said that for ethical reasons he was not involved with Lexeo.
Dr. Robert C. Green, a medical geneticist at Harvard who has studied how people respond to knowing their APOE4 status, cautioned against jumping to conclusions based on so little data from such a small study. However, he is not ready to dismiss it out of hand.
“It could be a Hail Mary treatment idea for Alzheimer’s disease,” he said. But “as a proof of concept,” he said, “I’m impressed.”
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