R. Nolan Townsend, Sandi See Tai, MD, and Kim G. Johnson, MD, on Gene Therapy for APOE4 Homozygous Alzheimer Disease
The 3 experts discussed Lexeo Therapeutics’ LX1001 gene therapy trial that demonstrated promising safety and biomarker effects in patients with early-stage Alzheimer disease.
This interview originally appeared on our sister site, NeurologyLive®.
"APOE4 homozygotes have no good treatment options right now, and this trial offers a potential treatment that provides hope for patients and their families.”
Risk for Alzheimer disease (AD) is known to be strongly associated with apolipoprotein E (APOE) polymorphisms. Research demonstrates that people homozygous for APOE4 have a 14.5-fold higher risk for late-onset AD than those who are homozygous for APOE3. In addition, those who are heterozygous for APOE2/E4 are at a 2.6-fold increased risk, thus pointing to a the potential of a protective role for APOE2. Lexeo Therapeutics' LX1001, an investigational adeno-associated virus vector-based gene therapy, is intended to provide a copy of the APOE2 gene to the cells of the central nervous system in patients with AD who are homozygous for APOE4. As such, the approach is expected to convert the genotype of transduced cells to APOE2/E4 and to in turn slow disease progression.1
LX1001 is currently being evaluated in a phase 1/2, open-label, dose-finding clinical trial (NCT03634007). Data from the study presented at the 2024 Clinical Trials on Alzheimer’s Disease (CTAD) conference, held October 29 to November 1, in Madrid, Spain, showed that LX1001 was generally safe and well-tolerated, and demonstrated a dose- and time-dependent effect on expression of APOE2. Furthermore, a reduction in several cerebrospinal fluid (CSF) AD tau biomarkers and changes on Tau PET suggested a treatment effect of the gene therapy on tau, which researchers note is a critical component in the pathobiology of AD.2
At CTAD 2024, R. Nolan Townsend, chief executive officer at Lexeo, coauthor Sandi See Tai, MD, chief development officer at Lexeo, and lead author Kim G. Johnson, MD, the division chief of memory disorders at Duke University, sat down with CGTLive®'s sister site NeurologyLive® to speak about some of the key safety findings from the trial. During the conversation, the trio also talked about how the APOE2 gene delivery impacted amyloid and tau biomarkers in trial participants, as observed in the study findings. Additionally, the experts spoke about the significance of targeting those homozygous for APOE4 with gene therapy in the AD treatment landscape.
