Gene Therapy Progress in Alzheimer’s Treatment: Lexeo Therapeutics’ APOE4-Associated Alzheimer’s Trial Shows Promise

Lexeo Therapeutics has announced promising interim results from its Phase I/II trial of LX1001, an innovative gene therapy targeting Alzheimer’s disease (AD) in patients with the APOE4 genetic variant. If successful, LX1001 could become the first approved gene therapy for Alzheimer’s, offering a much-needed option for a high-risk population with limited treatment alternatives.

The Role of APOE in Alzheimer’s

Alzheimer’s disease risk is significantly influenced by genetic factors, including the apolipoprotein E (APOE) gene. While most people have the neutral APOE3 variant, about 15–25% carry at least one copy of APOE4, which sharply increases the likelihood of developing Alzheimer’s. Unfortunately, patients with two APOE4 copies are at particularly high risk and have a faster disease progression. Current antibody treatments, like Biogen’s and Eisai’s Leqembi and Lilly’s Kisunla, are not suitable for APOE4 carriers due to increased risks of amyloid-related imaging abnormalities (ARIA).

Lexeo’s Gene Therapy Approach

Lexeo’s LX1001 utilizes adeno-associated virus (AAV) vectors to deliver a protective APOE2 allele directly into the brains of APOE4 homozygous patients. The APOE2 protein may slow or halt Alzheimer’s progression, providing a groundbreaking new therapeutic approach for those unable to receive standard antibody treatments. In this trial, 15 patients with mild-to-moderate AD symptoms received LX1001 across four dosage levels.

Promising Results

The interim results have shown that LX1001 was generally well tolerated, with no ARIA cases reported. Some of the encouraging outcomes include:

1. Increased APOE2 Protein Expression: Patients exhibited dose- and time-dependent increases in cerebrospinal fluid APOE2, indicating durable gene expression up to 12 months post-treatment.
2. Stabilized Amyloid Pathology: Most patients saw minimal changes in amyloid PET and other markers.
3. Reduced Tau Biomarkers: A significant reduction in cerebrospinal fluid tau protein, a critical Alzheimer’s biomarker, was observed in the majority of patients.
4. Safety Profile: No severe adverse events directly linked to LX1001 were observed, except one case of mild hearing loss, which is under investigation.

These results underscore LX1001’s potential in addressing the unique challenges of treating APOE4-associated Alzheimer’s, as noted by Dr. Kim Johnson of Duke University School of Medicine: “APOE4 homozygotes face significantly higher Alzheimer’s risks and progression rates, with increased ARIA susceptibility to available therapies. These interim findings suggest LX1001’s unique therapeutic potential to stabilize or slow disease pathology safely.”

Next Steps

Lexeo Therapeutics will continue to collaborate with the FDA on the LX1001 trial, with further updates expected in 2025. The company is also exploring next-generation therapies, LX1020 and LX1021, aimed at enhancing APOE2 expression and directly suppressing APOE4’s effects.

If fully realized, LX1001 and related gene therapies could offer a transformative option for Alzheimer’s patients genetically predisposed to this devastating disease.

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