Gene therapy could treat Alzheimer’s disease

Alzheimer’s disease starts slowly at first — a missed name, a forgotten outing, a misplaced key. But as the disease continues to take root in the brain, memory loss and cognitive impairments become more severe. Reversing these deficits with medication has proven to be a difficult task for the pharmaceutical industry.

After many decades of work focusing on the amyloid hypothesis led to treatments with only limited success, some researchers are now looking outside the box to a new approach for Alzheimer’s disease: gene therapy (1). 

“In the Alzheimer’s world, there’s a huge argument that goes on for years in terms of is it amyloid or is it tau, or is it both, or something else? We’re ignoring that. What we’re doing is going proximal to that by dealing with the genetics,” said Ronald Crystal, a pulmonary doctor and gene therapy researcher at Weill Cornell Medicine. “We’re trying to convert the genetics from bad genetics to good genetics in the brain.”

We’re trying to convert the genetics from bad genetics to good genetics in the brain.”
– Ronald Crystal, Weill Cornell Medicine

Other researchers are also using gene therapy to deliver genetic instructions to make protective proteins that promote the health and survival of neurons to help stave off disease. These approaches all have the advantage of using viral vectors that make it across the blood-brain barrier, something that the recently approved monoclonal antibody treatments have struggled to do.

For gene therapy, “the advantage is you can put it directly into the organ that you want to deliver the protein to, and it’s forever,” said Crystal.

Providing a protective gene

Crystal was one of the first scientists to begin studying gene therapy back in the 1980s, first focusing on pulmonary applications (2). In the last decade, Crystal and his colleagues began working on a gene therapy approach to Alzheimer’s disease that targets the apolipoprotein E (APOE) gene, which codes for a protein that the brain uses to carry lipids. There are three versions of the gene, and unfortunately the APOE4 allele present in about 20 percent of the population increases the risk for Alzheimer’s disease (3). For individuals with two copies of the APOE4 allele, their risk goes up to 60 percent by age 85 (4). Most of the population has the neutral APOE3 allele, and just five percent of the population has the APOE2 allele (3).

“If you’re lucky enough to have parents that give you APOE2, then you have a decreased risk. If you do develop Alzheimer’s, it develops at a later age, and it is less severe,” said Crystal. Thus, Crystal and his team wondered whether delivering the APOE2 gene to individuals with the highest risk would offer protection against Alzheimer’s disease.

To deliver APOE2 to the brain, they used adeno-associated virus (AAV) serotype RH10 injected into the cerebrospinal fluid (CSF) between C1 and C2 vertebra of mice. Based on that work, Lexeo Therapeutics began a Phase 1/2 clinical trial that tests the therapy in humans by delivering the viral vectors in the same place. It’s an invasive therapy, but the goal is to administer it just once and have the effects last for the rest of someone’s life.

In 2022, Lexeo Therapeutics announced early results showing that patients with Alzheimer’s disease who have two copies of the APOE4 allele successfully expressed the APOE2 protein in their CSF (5). The patients also showed decreases in tau protein levels and had no significant adverse safety events. The company completed enrollment last year and plans to release more data later this year.

“The challenge is understanding how those [early results] translate to the longer term endpoints, which is actually changing or slowing progression,” said Sandi See Tai, Chief Development Officer at Lexeo Therapeutics. “That certainly takes a little longer and much larger trials to show that, but at least what’s really encouraging is having the biomarkers that are able to suggest that there are early therapeutic effects here.”

Lexeo Therapeutics is also developing two additional versions of their gene therapy for Alzheimer’s disease in preclinical models. One version adds a microRNA to suppress APOE4 in the brain to see if that offers any additional efficacy, and another version adds a Christchurch variant to the APOE2 gene, since the variant has a protective effect against Alzheimer’s disease in people with the APOE3 allele (6). See Tai said that they will continue to study all three gene therapies in parallel to determine which one has the most benefit for patients, while still moving forward with the original version already in clinical trials. “There is such a significant unmet need here that we just think about what’s the clearest path and the fastest way to get a potentially effective and safe treatment to patients,” said See Tai.

If the treatment proves to be effective, Crystal hopes that in the future it could even be used as a preventative treatment in people who are homozygotes for the APOE4  allele before they develop symptoms. “In an ideal world, what you want to do is treat as soon as possible. Why let the pathogenesis smolder subclinically?” he said.

Rebuilding the brain

Other gene therapies for Alzheimer’s disease don’t focus on genetics at all. Mark Tuszynski, a neurologist and neuroscientist at University of California, San Diego (UCSD), is leading a Phase 1 clinical trial with neurosurgical oncologist Bradley Elder and neurosurgeon Kryś Bankiewicz of Ohio State University to test whether introducing brain-derived neurotrophic factor (BDNF) could prevent neurons from dying in people with Alzheimer’s disease.

BDNF is a growth factor present in the brain throughout life that has protective effects on neurons and creates new synaptic connections between neurons (7). Studies from Tuszyznki’s laboratory have shown that BDNF delivered to the entorhinal cortex and hippocampus, brain regions known to be integral for memory, improves learning and memory and protects neurons in rodent and primate models of Alzheimer’s disease (8,9). Tuszynski explained that the goal of using growth factors is to rebuild the brain and repair damage after Alzheimer’s disease has taken hold. “That’s exactly a place where BDNF comes in conceptually because BDNF rebuilds these circuits. Its normal role in the brain is to maintain circuits. And we give much more than a normal amount of BDNF; we give about 500-fold levels,” he said.

Tuszynski’s team chose a gene therapy approach to introduce BDNF into the brain because infusing BDNF into the CSF causes it to spread all over the brain, which can lead to adverse effects when BDNF stimulates sensory neurons responsible for pain or satiety. “We introduced the gene locally into the part of the brain that we’re trying to treat, and that makes the BDNF. It’s secreted from the cell, it stays in the local environment, and it gets transported down axons into the hippocampus, where it also exposes the hippocampal circuits to the growth factor,” said Tuszynski.

The clinical trial at UCSD started over a year ago and has enrolled three patients so far. They don’t have any long-term data yet, but Tuszynksi described a positron emission tomography (PET) scan in one patient that showed that the metabolic activity of the treated side of the brain was preserved after one year, while the metabolic activity on the untreated side declined. “That’s just one patient. You can’t draw any conclusions from one, but that’s a signal that suggests we may have engaged our biological target.” 

That signal is an improvement over a previous Phase 2 clinical trial from Tuszynski’s group that used gene therapy to deliver nerve growth factor (NGF) to patients with Alzheimer’s disease. In that study, the NGF treatment failed to show any impact on clinical outcomes (10). After the trial ended, the team analyzed the brains of ten participants who passed away and found that “in more than 80 percent of the sites, the growth factor did not reach the target part of the brain,” said Tuszynksi. “It was clear we had to improve our methods.”

Tuszynski then teamed up with Bankiewicz, who developed a magnetic resonance imaging (MRI)-guided gene therapy delivery system. Together, they designed MRI-guided technology to target the entorhinal cortex and found that it was successful in nonhuman primates. “We can see in real time as we’re infusing that we’ve hit the right target, and that we’re spreading the growth factor over the desired volume of distribution of the entorhinal cortex,” said Tuszynski. He added that they plan to use this MRI-guided technology to deliver their BDNF gene therapy for now, since BDNF more directly acts on the neurons to prevent cell death while NGF acts on cells that regulate neurons in the cortex.

The challenge for this type of gene therapy, Tuszynski noted, will be how to feasibly offer it to lots of patients, as it can’t be given intravenously and instead requires guidance with MRI. His team is working on a computed tomography (CT) option, which he said would be cheaper and quicker. 

Mayur Parmar, a neuroscientist and pharmacologist at Nova Southeastern University who formerly worked on the preclinical work for the APOE2 gene therapy with Paul and Crystal, said that the major advantage of gene therapy is that it can target multiple pathologies to go beyond the effects of amyloid plaques. With both the APOE2  and BDNF gene therapies in clinical trials now, “we might be able to benefit a larger population of Alzheimer’s disease, maybe early stage, rather than a very specific population,” he said.

The main challenges that Parmar sees for Alzheimer’s disease gene therapies are the same ones facing FDA-approved gene therapies. They include making sure that the body’s immune system does not target the AAV vectors used to deliver the gene therapy through neutralizing antibodies and ensuring that patients will be able to afford the therapies if they are approved.

Parmar only began studying Alzheimer’s disease after working on a related research proposal during his qualifying exam in his doctoral studies. “There was just that moment where I was trying to write a sentence … thinking that I cannot think of my mom forgetting me [if she had Alzheimer’s disease],” he said.

Others echoed this sentiment. “We all have family members or at least know someone who’s been impacted by this disease. And so, for me, what keeps me engaged is the possibility of getting a treatment to patients that can hopefully significantly shift the treatment paradigm and really make a huge difference for patients,” said See Tai. 

As a neurologist who treats patients, the potential for gene therapies to advance Alzheimer’s disease treatment is also front of mind for Tuszynski. “Seeing patients is my frequent reminder about why we’re doing this, that we just have to do better,” he said.

References

1. Walsh, S., Merrick, R., Richard, E., Nurock, S. & Brayne, C. Lecanemab for Alzheimer’s disease. BMJ 379, o3010 (2022).
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3. Wu, L. & Zhao, L. ApoE2 and Alzheimer’s disease: time to take a closer look. Neural Regen Res  11, 412–413 (2016).
4. Fortea, J. et al. APOE4 homozygosity represents a distinct genetic form of Alzheimer’s disease. Nat Med  30, 1284–1291 (2024).
5. LEXEO Therapeutics Announces Positive Initial Data from Ongoing Phase 1/2 Clinical Trial of AAV-based Gene Therapy Candidate LX1001 in Patients with Alzheimer’s Disease. Lexeo Therapeutics (2022). at https://www.lexeotx.com/post/lexeo-therapeutics-announces-positive-initial-data-from-ongoing-phase-1-2-clinical-trial-of-aav-based-gene-therapy-candidate-lx1001-in-patients-with-alzheimers-disease/
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10. Rafii, M.S. et al. Adeno-Associated Viral Vector (Serotype 2)–Nerve Growth Factor for Patients With Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol  75, 834–841 (2018).