New gene therapies hold promise for treating Alzheimer’s disease, aiming to heal the brain with a single dose of beneficial genetic material.
While Alzheimer’s typically starts subtly – a missed name,forgotten appointment,misplaced keys – it progressively leads to severe memory loss and cognitive decline. Traditional medications have struggled to reverse these devastating effects,leaving scientists searching for new approaches.
Emerging from decades of research focused on amyloid plaques, some researchers are now exploring the power of gene therapy for Alzheimer’s. Rather than debating the amyloid or tau protein hypothesis, gene therapy focuses on directly addressing the genetic underpinnings of the disease. This novel approach aims to convert harmful genetics into beneficial ones directly within the brain.
"We’re trying to convert the genetics from bad genetics to good genetics in the brain," says Ronald Crystal, a renowned pulmonary doctor and gene therapy researcher at Weill Cornell Medicine.
other researchers are leveraging gene therapy to deliver instructions that encourage the production of protective proteins, fostering neuron survival and shielding against disease progression. These therapies boast an advantage as the viral vectors used can readily cross the blood-brain barrier, a challenge for recently approved monoclonal antibody treatments.
"The advantage is you can put it directly into the organ that you want to deliver the protein to, and it’s forever," emphasizes Crystal.
A Protective Gene
Crystal, a pioneer in gene therapy, first began his work in the 1980s, initially focusing on lung applications. In recent years, he and his team have dedicated thier efforts to developing a gene therapy for Alzheimer’s that targets the apolipoprotein E (APOE) gene. This gene directs the production of a protein crucial for carrying lipids within the brain. There are three versions of APOE, and regrettably, individuals carrying the APOE4 allele (found in about 20% of the population) are at increased risk for Alzheimer’s disease.
those with two copies of APOE4 face a staggering 60% risk of developing Alzheimer’s by age 85. In contrast, individuals with the APOE2 allele exhibit a decreased risk and experience a later onset with milder disease progression.
Intrigued by these discoveries, Crystal and his colleagues wondered if delivering the APOE2 gene to high-risk individuals could offer protection. They used adeno-associated virus (AAV) serotype RH10 injected into the cerebrospinal fluid to deliver the gene to mice. Based on these findings,Lexeo Therapeutics launched a Phase 1/2 clinical trial,administering the viral vectors in the same manner to test the therapy in humans. This invasive treatment aims for a single management, with the effects lasting for life.
In 2022, Lexeo Therapeutics announced promising early results from the clinical trial. Patients with two APOE4 gene copies successfully expressed the APOE2 protein in their cerebrospinal fluid. these promising results also showed a decrease in tau protein levels with no notable adverse events. The trial’s enrollment was completed last year, with a release of more extensive data anticipated later this year.
"the challenge is understanding how those early results translate to the longer-term endpoints, which is actually changing or slowing progression," See Tai explains. "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 investigating two additional gene therapy versions for Alzheimer’s in preclinical models. One version incorporates a microRNA to suppress APOE4 production in the brain. Another variation includes the Christchurch variant, known to possess a protective effect against Alzheimer’s in individuals with the APOE3 allele.
See Tai explains that researchers will continue to evaluate all three therapies concurrently to determine which offers the most significant benefit, while together moving forward with the original, now 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," notes See Tai.
Dr.Crystal envisions that if the treatment proves effective, it could eventually be used preventively for individuals with two copies of the APOE4 allele before they develop symptoms.
Another Gene Therapy pendekatan for Alzheimer’s disease looks beyond genetics. Mark Tuszynski, a neurologist and neuroscientist at UCSD, is leading a Phase 1 clinical trial with surgical oncologist Bradley Elder and neurosurgeon Krystof Bankiewicz of Ohio State University.
Their focus is on investigating whether introducing brain-derived neurotrophic factor (BDNF), a growth factor naturally present in the brain, can prevent neuron death in Alzheimer’s patients.
BDNF is crucial for neuron protection and creating synaptic connections between neurons. Years of research in Tuszynski’s lab have shown that BDNF, delivered to the entorhinal cortex and hippocampus (brain regions vital for memory), improves learning, memory, and protects neurons in both rodent and primate models of Alzheimer’s.
tuszynski notes that the goal isn’t just to protect existing neurons – it’s to actually rebuild the brain after alzheimer’s disease has taken hold. "That’s exactly a place where BDNF comes in conceptually as 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," the scientist explains.
tuszynski’s team chose gene therapy for delivering BDNF to the brain because infusing BDNF directly into the cerebrospinal fluid would spread to other parts of the brain, potentially causing side effects if 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 habitat, and it gets transported down axons into the hippocampus, where it also exposes the hippocampal circuits to the growth factor,” Tuszynski explains.
Three patients have enrolled in their clinical trial.though long-term data is unavailable, a positron emission tomography (PET) scan showed positive results in one patient: the metabolic activity of the treated side of the brain was preserved after one year, while 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.
Tuszynski teamed up with Bankiewicz, who developed an MRI-guided gene therapy delivery system. Together, they designed a method using MRI guidance to precisely target the entorhinal cortex in nonhuman primates, ensuring the growth factor is effectively distributed.
"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," says Tuszynski.
the challenge, notes Tuszynski, will be making this therapy readily accessible to a large patient population. While BDNF directly acts on neurons for neuron protection, NGF acts on cells that support neurons.The team is developing a computed tomography (CT) option for guidance, which would be more cost-effective and faster.
Mayur Parmar, a neuroscientist and pharmacologist at Nova Southeastern University who previously worked on preclinical work for the APOE2 gene therapy with Cristal, says that the main advantage of gene therapy is it can target multiple pathologies, offering broader applicability than treatments focused solely on amyloid plaques.
Both the APOE2 and BDNF gene therapies are in clinical trials, suggesting a potential to benefit a larger Alzheimer’s population, likely at earlier stages.
While there are challenges ahead, such as overcoming the body’s immune response and ensuring affordability, the team remains optimistic.
For many involved in these gene therapy efforts, the motivation comes from the possibility of significantly impacting the treatment paradigm for Alzheimer’s disease. "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," See Tai explains. The potential to help patients
drives both researchers and clinicians developing these therapies.
What are the key differences between gene therapy and traditional Alzheimer’s treatments?
Interview between Time.news Editor and Dr. Ronald Crystal, Gene therapy Researcher at Weill Cornell Medicine
Editor: Welcome, Dr.Crystal! It’s a pleasure to have you here today to discuss the exciting advances in gene therapy for Alzheimer’s disease. To start, can you explain how gene therapy differs from traditional treatments for Alzheimer’s?
Dr. Crystal: Thank you for having me! Traditional treatments for Alzheimer’s primarily focus on alleviating symptoms rather than addressing the underlying causes of the disease. They frequently enough target amyloid plaques or tau proteins, but so far, those strategies have had limited success in reversing cognitive decline. Gene therapy, on the other hand, allows us to intervene at the genetic level. We aim to convert harmful genetics into beneficial ones right within the brain.
Editor: that sounds revolutionary! could you elaborate on how you plan to accomplish this change?
dr. Crystal: Absolutely. One key focus of our research is the apolipoprotein E (APOE) gene. People with the APOE4 allele are at increased risk for Alzheimer’s, while those with the APOE2 allele have a protective effect. Our goal is to deliver the APOE2 gene to individuals at high risk, essentially providing them with a genetic safeguard against developing Alzheimer’s. We use adeno-associated virus (AAV) vectors to deliver the gene directly into the cerebrospinal fluid, wich can then spread throughout the brain.
Editor: That’s fascinating! What have been some of the initial findings from your clinical trials?
Dr. crystal: In 2022, we released promising preliminary results where patients who have the two copies of the APOE4 genotype successfully expressed the APOE2 protein in their cerebrospinal fluid. Moreover,we observed reduced levels of tau proteins,which are often linked to neurodegeneration. Importantly, these results came without notable adverse events, suggesting that this approach is safe.
Editor: It sounds promising, but you mentioned the challenge of translating these early results into long-term benefits. Can you explain that a little more?
Dr. Crystal: Certainly. While early biomarkers indicate that our therapy may have immediate effects, such as protein expression and reduced tau levels, we need larger trials over longer durations to ascertain whether these changes effectively slow or prevent disease progression. This longitudinal research is crucial to demonstrate the therapy’s overall efficacy.
Editor: Your research is clearly complex. Are there other avenues of gene therapy that you are exploring, perhaps in collaboration with other institutions?
Dr. Crystal: Yes, indeed! Alongside our work on the APOE gene therapy, Lexeo Therapeutics is also investigating additional gene therapy strategies. As a notable example,one approach involves using microRNA to suppress APOE4 production in the brain. Another utilizes the Christchurch variant, which may offer protective benefits for individuals with the APOE3 allele.
Editor: It seems like you’re exploring multiple angles to tackle Alzheimer’s! How optimistic are you about the potential of gene therapy in this field?
Dr. Crystal: I’m cautiously optimistic.There is a meaningful unmet medical need for effective Alzheimer’s treatments, and if our therapies prove effective, they could even be used preventively for those at high genetic risk before symptoms appear. The potential impact on patients’ lives could be transformative.
Editor: Switching gears a bit, I understand that other researchers, such as Dr. Mark Tuszynski, are taking a different approach with brain-derived neurotrophic factor (BDNF). How do you see these different strategies complementing each other?
Dr. Crystal: Each approach brings valuable insights to the table. While my team is focusing on genetic modifications, Dr. Tuszynski’s work on BDNF is crucial because it addresses neuron health and connectivity directly.The combination of strategies creates a multi-faceted attack on Alzheimer’s, enriching our understanding and the overall therapeutic landscape.
Editor: It’s all very intriguing! Before we conclude, what message or hope would you like to convey to those affected by Alzheimer’s disease?
Dr. Crystal: I want individuals and families affected by Alzheimer’s to know that we are deeply committed to finding effective treatments. The advances in gene therapy offer real hope for a future where Alzheimer’s can be not only treated but prevented. Every step we take in research is aimed at making a meaningful difference in the lives of those facing this challenge.
Editor: Dr. Crystal, thank you so much for your insights and for sharing the groundbreaking work you and your team are doing. We look forward to following your progress!
Dr. Crystal: Thank you! It’s been a pleasure discussing this vital topic. Together, we can hope for a brighter future in Alzheimer’s treatment.