Discovery, Gene Therapy

Cornell researchers to launch early trial of gene therapy aimed — ultimately — at preventing Alzheimer’s

The notorious difficulty — if not impossibility — of reversing or slowing the progression of Alzheimer’s has pushed researchers to study much earlier stages of the disease, and the potential of treating patients before they show signs of brain damage. But can they go even earlier than that — by taking a prevention approach based on a genetic driver of the disease?

Ronald Crystal

Doctors at Weill Cornell Medicine are giving it a try with a gene therapy designed to flood the brains of high-risk patients with a low-risk version of the APOE gene, thereby knocking down their risk of getting Alzheimer’s to just average. In three months — pending manufacturing clearance — they will begin a 15-person trial to test if their infusion can indeed lead to the right mix of genes (and subsequent production of proteins) in the brain.

Targeting the gene, principal investigator Ronald Crystal told MIT Tech Review, means his team doesn’t need to commit to any of the theories of what actually causes Alzheimer’s, whether it’s the dominant but increasingly shaky amyloid-beta hypothesis or the variety of new targets cropping up in recent years.

“What attracts us to Alzheimer’s is that the genetic epidemiology is so obvious,” Crystal, a professor of genetic medicine, said. “So the strategy is, can we bathe the brain in E2? We have the infrastructure to do it, so we thought, why not? It gets around the problem of the mechanism of the disease.”

By E2, he is referring to the APOE2 gene, which is thought to lower a person’s risk of developing Alzheimer’s. For the trial, they are recruiting patients with two copies of the APOE4 gene, the version of the apolipoprotein E gene that portends the nasty memory-wasting ailment. They will then inject billions of viruses containing APOE2 to the patients’ spinal cords.

Specifically, Crystal told me, they are using the AAV serotype rh.10 — a kind they have previously administered to children with Batten disease through direct infusion to the brain in a separate trial. So while “you never know until you do the studies in humans,” he is optimistic that safety wouldn’t be a major concern.

After answering the big questions about safety, the measure of efficacy will go as far as detecting the function of the gene, since the therapy is unlikely to alter the conditions for a group of patients already diagnosed with some form of cognitive impairment or dementia due to Alzheimer’s.

“The concept is rational,” Crystal told MIT Tech Review. “Whether it works in a human is another thing.”

Notably, only about 2% of the world’s population are APOE4/4 homozygotes, although one in four people carry a single copy, according to the Banner Alzheimer’s Institute.

Crystal acknowledged the small percentage of potential Alzheimer’s patients with both copies of APOE4, but suggested that E3/E4 heterozygotes, who are also at risk (albeit a smaller one) for the disease, add to the population that the gene therapy can ultimately treat.

Nevertheless, APOE4 is a well-known risk factor that has been popping up in Alzheimer’s news a number of ways. Biogen and Eisai, to pick a recent example, were bashed hard when analysts found out they had pulled APOE4 carriers from a treatment arm of their big BAN2401 study, possibly skewing the results in the drug’s favor.

And then there’s Alzheon, whose plan to revive a once-failed drug by focusing on a population of Alzheimer’s patients with two copies of the APOE4 gene has been met with cold glares from public investors.

Yet, because the function of the APOE gene remains somewhat mysterious (there’s some evidence it’s associated with amyloid-beta deposition), there have been few attempts to tinker with it directly. One exception is the biotech startup E-scape Bio, which has a plan to restructure APOE4 proteins into APOE3 — the “medium risk” type.

While both Voyager and J&J are also working on gene therapies — mostly still in preclinical stage — to combat Alzheimer’s, their focus is on triggering the production of therapeutic antibodies.

The almost brute force approach of Cyrstal’s upcoming study, then, makes it a somewhat novel upstream approach aimed at prevention.

The Alzheimer’s Drug Discovery Foundation has committed $3 million to the project, its largest grant to date according to MIT Tech Review. It’s expected to wrap at the end of 2021.


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Research Scientist - Immunology
Recursion Pharmaceuticals Salt Lake City, UT
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Atlas Venture Cambridge, MA

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