Novel Gene Therapy Approach in ADDF-Funded Trial Reports Promising Early Results

Lexeo Therapeutics announced positive early data this week from an ADDF-funded Phase 1/2 clinical trial of LX1001, a unique treatment approach that targets the underlying genetics of Alzheimer’s disease. These initial results are promising, indicating that a gene therapy approach is safe and shows target engagement, generating levels of a gene called APOE2 that has the potential to protect those with a pre-existing genetic risk for Alzheimer’s.

The ADDF began funding this research in the laboratory of gene therapy pioneer Dr. Ronald Crystal at Weill Cornell Medical Center in 2004 and continues to support it in clinical trials today. “Gene therapy is a promising and complex research area, which makes Lexeo’s results, while preliminary, all the more exciting,” said Dr. Howard Fillit, Co-Founder and Chief Science Officer of the Alzheimer’s Drug Discovery Foundation (ADDF).

While the efficacy data are intriguing, this trial is primarily testing dose levels of LX1001 and assessing its safety and tolerability. These are key measures in gene therapy, where delivering genes to the exact tissue target can be challenging. Dr. Crystal, Founder and Chief Scientific Adviser of Lexeo Therapeutics, has likened this work to “delivering a message in a bottle.” In the case of LX1001, the APOE2 gene is carried on a benign virus called AAV that is then modified to ensure it travels to the brain where it can drop off its message—the APOE2 gene.

“If the study continues to generate positive findings, this would be a big win for Alzheimer’s patients. The promise of gene therapy is that a one-time treatment could have long-lasting effects as the protective genes live on in the brain, conferring durable and perhaps even permanent protection against neurodegeneration,” added Dr. Fillit.

The LX1001 trial enrolled patients who carry the APOE4 gene, which greatly increases the risk of Alzheimer’s disease, and delivered a protective gene called APOE2 into their brains. The hypothesis is that therapeutic levels of APOE2 can fix malfunctioning genes in the brain’s neurons and slow or even halt Alzheimer’s progression.

Researchers measured the impact of LX1001 in patients’ cerebrospinal fluid (CSF). They found protective levels of APOE2 protein in all four patients evaluated three months after treatment, and the APOE2 level remained increased in two of the patients 12 months after treatment. They also noted declines in downstream biomarkers of Alzheimer’s disease—total tau and P-tau protein levels in the latter two patients.

More data from this study is expected in the second half of 2022, including an additional 12-month follow up on the first round of patients and new data from a second patient cohort.