Can Gene Therapy Change the Course of Alzheimer’s?

Back in 2001, a 60-year-old woman in the early stages of Alzheimer’s underwent an 11-hour surgical procedure at the University of California San Diego’s hospital in La Jolla as part of an experimental treatment. The surgeons injected her cells with an extra gene aiming to produce a natural brain-survival molecule, called nerve growth factor (NGF), to protect her dying neurons. 

The woman was the first person to ever receive an experimental gene therapy aimed at slowing the progression of Alzheimer’s. The Phase 1 trial showed the approach was safe and feasible, prompting neurologist Dr. Mark Tuszynski, who ran the pilot study to set up a larger trial. 

Gene therapy would have advantages over traditional pills or infusions, since it only requires a one-time treatment. However, in the follow-up trial he conducted, the gene therapy did not slow cognitive or functional decline.

Researchers including Tuszynski haven’t given up on gene therapy. Over the past two decades scientists have developed better molecular tools and MRI-based guidance that ensures these therapies are injected into the right part of the brain. 

Gene therapy is “making its first breakthroughs in human medicine,” Tuszynski told Being Patient. After successes in other diseases of the nervous system, including spinal muscular atrophy and congenital blindness, he hopes that Alzheimer’s might be next. 

Rewriting the genetic code to add new genes

The first gene therapy trials decades ago, like Tuszynski’s, added extra genes into the DNA.

In his Phase 1 trial, the researchers took patients’ own cells and added in a gene to produce NGF before injecting them into the brain. For the Phase 2 trial, they figured out how to package the gene into an adeno-associated virus, a harmless infectious agent that delivers the genes to specific regions of the brain. 

Many of today’s gene therapies also use viruses to deliver new genes. Lexeo Therapeutics is targeting the ApoE gene to modulate the disease. The gene comes in multiple variants with different effects on Alzheimer’s risk: People who carry two copies of the ApoE4 version of the gene have a 60 percent lifetime risk of developing Alzheimer’s, meanwhile, ApoE2 provides protection. 

For instance, the company completed an early trial of LX1001, injecting a gene therapy into the spinal canal that adds a copy of the ApoE2 gene into brain cells to provide extra protection.

Tuszynski is also running a new early-stage gene therapy trial which involves delivering another nerve growth factor called brain-derived neurotrophic factor (BDNF). Surgeons will use MRI-guidance to ensure the gene therapy gets to the right place.

NGF only protects the neurons that produce the chemical acetylcholine. “BDNF treated a more important cell type,” said Tuszynski, “neurons in the cortex of the brain” that handle memory and higher cognitive functions. 

“We’ve treated nine of 12 patients so far, and we don’t have information yet on how it’s affecting memory,” said Tuszynski. But so far, brain imaging is promising: One sign of Alzheimer’s is slowed metabolism in the brain, and so far, the treatment looks like it’s reversing these changes. 

“That doesn’t mean it will help memory or be effective for the disease,” he said, “but it’s a hopeful sign.” 

The study will finish in 2027, and if the results show promise, it will lead to a larger trial. 

Gene silencing therapies in the works for Alzheimer’s

Think of DNA as a cookbook and individual genes as recipes. To make a protein, cells need to copy down the recipe and take it into the kitchen. Cells write the recipe into a molecule called RNA. 

Some gene silencing therapies prevent the cooks from being able to read the RNA, stopping the protein from being formed. Scientists are testing this strategy to target genes that produce the beta-amyloid proteins and tau tangles that define Alzheimer’s.

Alnylam Therapeutics is in the early stages of testing a treatment called ALN-APP, which binds to the RNA for the APP gene to reduce the production of amyloid proteins. The current trial to determine the ideal dosing and measure its safety and effectiveness will finish in 2029. 

Biogen is working on a drug called BIIB080 that aims to stop tau proteins from being made. The drug sticks to tau RNA to stimulate its destruction. The therapy is currently in Phase 2 trials, which will finish in 2029. 

The future of Alzheimer’s gene therapy

Boris Kantor, a professor at Florida State University, is developing a different strategy called epigenome editing. Rather than editing the genome or silencing RNA, it adds chemical marks to the DNA that prevent certain recipes from being copied as often. 

Right now, Kantor is targeting the Alzheimer’s risk gene ApoE4 in animal models. 

“You get Alzheimer’s through hyperfunction or hyperactivity of the ApoE4 protein,” he told Being Patient. When ApoE4 is working overtime in the brain, it kicks off the disease processes linked to Alzheimer’s. A one-time treatment could reduce the levels of ApoE4 by 80 percent. He’s hoping within the next five to ten years, epigenome editing will be tested in human trials. 

With many scientists working to develop better tools to add, edit, and silence genes, there is more momentum than ever before for developing a working Alzheimer’s gene therapy.