Gene therapy is gaining traction as a potential treatment for Alzheimer's disease, offering a new approach that moves beyond traditional targets like amyloid plaques. Researchers are exploring ways to use gene therapy to modify genetic risk factors and enhance neuronal survival, with early clinical trials showing promising results.
Targeting Genetic Risk Factors with APOE2 Gene Therapy
Ronald Crystal at Weill Cornell Medicine is focusing on the apolipoprotein E (APOE) gene, a known genetic risk factor for Alzheimer's. The APOE4 allele, present in about 20% of the population, significantly increases the risk of developing the disease. Crystal's approach involves delivering the APOE2 gene, a protective variant, to individuals with the APOE4 allele. "We're trying to convert the genetics from bad genetics to good genetics in the brain," Crystal explained.
Lexeo Therapeutics is currently conducting a Phase 1/2 clinical trial using an adeno-associated virus (AAV) vector to deliver the APOE2 gene into the cerebrospinal fluid of Alzheimer's patients with two copies of the APOE4 allele. Early results from 2022 indicated successful expression of the APOE2 protein in the CSF, along with decreases in tau protein levels and no significant adverse safety events. Sandi See Tai, Chief Development Officer at Lexeo Therapeutics, noted, "What's really encouraging is having the biomarkers that are able to suggest that there are early therapeutic effects here."
Lexeo is also developing additional gene therapy versions, including one that suppresses APOE4 and another that adds a Christchurch variant to the APOE2 gene, aiming to maximize therapeutic benefits.
Rebuilding Brain Circuits with BDNF Gene Therapy
Mark Tuszynski at the University of California, San Diego (UCSD), is taking a different approach by using gene therapy to deliver brain-derived neurotrophic factor (BDNF) to the brain. BDNF is a growth factor that supports neuronal survival and promotes synaptic connections. Tuszynski's Phase 1 clinical trial aims to rebuild brain circuits and repair damage caused by Alzheimer's disease.
The BDNF gene is delivered directly into the entorhinal cortex and hippocampus, brain regions crucial for memory. Tuszynski explained that this localized delivery helps avoid potential adverse effects associated with widespread BDNF infusion. Early data from one patient showed preserved metabolic activity in the treated side of the brain after one year, while the untreated side declined.
Tuszynski's team is using an MRI-guided gene therapy delivery system to ensure accurate targeting of the entorhinal cortex. This approach builds on previous work with nerve growth factor (NGF), where the treatment failed to show clinical impact due to poor delivery to the target brain regions.
Challenges and Future Directions
While gene therapy holds great promise for Alzheimer's disease, challenges remain. Mayur Parmar, a neuroscientist at Nova Southeastern University, highlighted the importance of addressing the immune response to AAV vectors and ensuring the affordability of these therapies. Tuszynski also noted the need to develop more feasible delivery methods, such as a CT-guided option, to make the treatment accessible to a larger patient population.
Despite these challenges, researchers are optimistic about the potential of gene therapy to significantly impact the treatment of Alzheimer's disease. As Tuszynski stated, "Seeing patients is my frequent reminder about why we're doing this, that we just have to do better."
