This Phase 1/2 open-label, dose-escalation clinical trial evaluated the safety, tolerability, and preliminary efficacy of LX1001, an adeno-associated virus (AAV) serotype rh.10 gene therapy vector expressing human APOE2, in participants who are homozygous for the APOE4 allele and have been diagnosed with Alzheimer's disease (AD). The study established the maximum tolerable dose across four ascending dose cohorts and generated initial evidence regarding APOE isoform conversion in the cerebrospinal fluid.
The trial ran from November 2019 to November 2024 and enrolled 15 participants across four dose levels. Participants completing the parent study were enrolled in the long-term follow-up study NCT05400330, which tracks safety and biomarker outcomes for up to 260 weeks post-administration.
| Field | Value |
|---|---|
| NCT ID | NCT03634007 |
| Status | Completed (November 2024) |
| Phase | Phase 1 / Phase 2 |
| Study Type | Interventional |
| Allocation | Non-randomized |
| Intervention Model | Sequential (dose escalation) |
| Masking | None (open-label) |
| Enrollment | 15 participants (actual) |
| Sponsor | Lexeo Therapeutics |
| Collaborators | Alzheimer's Drug Discovery Foundation, Weill Cornell Medicine |
| Start Date | November 2019 (actual) |
| Completion Date | November 2024 (actual) |
| Locations | K2 Medical Research (Maitland, FL), PPD Orlando (FL), Weill Cornell Medicine (NY), Duke University (NC) |
Homozygous APOE4 carriers represent the highest-risk population for Alzheimer's disease[1]:
The APOE2 isoform is associated with significantly reduced AD risk and multiple neuroprotective properties:
LX1001 delivers the APOE2 gene directly to the CNS via intrathecal AAVrh.10 administration, enabling persistent expression of APOE2 protein in the CSF and brain parenchyma. This approach:
| Parameter | Value |
|---|---|
| Agent | AAVrh.10hAPOE2 (LX1001) |
| Type | Adeno-associated virus serotype rh.10 |
| Gene Delivered | Human APOE2 complementary DNA (cDNA) |
| Route of Administration | Intrathecal injection |
| Vector Production | 293T cell-based producer system |
| Quantification | Droplet digital PCR (ddPCR) |
| Cohort | Dose | Participants | Description |
|---|---|---|---|
| Cohort 1 | 1.4×10^10 gc/mL CSF | ~3-5 | Low-dose initial safety |
| Cohort 2 | 4.4×10^10 gc/mL CSF | ~3-5 | Mid-dose escalation |
| Cohort 3 | 1.4×10^11 gc/mL CSF | ~3-5 | High-dose escalation |
| Cohort 4 | 1.4×10^14 gc (fixed dose) | ~3-5 | Fixed dose (~3.4×10^11 gc/mL CSF based on 409 mL average CSF volume) |
The AAVrh.10 serotype was selected for[2]:
| Measure | Time Frame | Description |
|---|---|---|
| Proportion of participants with treatment-emergent adverse events and serious adverse events | 1 year | Adverse events categorized and graded per CTCAE |
| Proportion of participants with treatment-emergent adverse events and serious adverse events at each dosage level | 1 year | Dose-stratified safety analysis |
The trial assessed multiple secondary endpoints including:
Screening Period (up to 42 days)
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Intrathecal LX1001 Administration (Day 0)
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Post-administration Follow-up (52 weeks per cohort)
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Safety monitoring: weeks 4, 8, 12, 26, 39, 52
CSF/blood biomarkers: weeks 4, 12, 26, 52
Amyloid PET: baseline and week 52
MRI: baseline and week 52
Cognitive assessments: baseline, weeks 26 and 52
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Completion → Enrollment in NCT05400330 (LTFU)
Independent Safety Review Committee evaluated data after each cohort:
The trial was completed in November 2024. Top-line results have been reported:
Detailed results will be published in peer-reviewed journals and presented at scientific conferences.
Following intrathecal administration, LX1001 transduces cells in the CNS, leading to sustained APOE2 protein expression:
Intrathecal AAVrh.10hAPOE2 administration
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Transduction of CNS cells (ependymal cells, meningeal cells, choroid plexus)
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Persistent APOE2 protein expression in CSF
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Isoform competition: APOE2 competes with endogenous APOE4 for lipid binding
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CSF APOE profile shifts from APOE4/APOE4 → APOE2/APOE4 heterozygote
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Neuroprotective effects across multiple pathways:
• Enhanced amyloid clearance (microglial degradation + perivascular transport)
• Reduced tau phosphorylation and aggregation
• Improved synaptic function and neuronal repair
• Decreased neuroinflammation
• Preserved blood-brain barrier integrity
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Disease modification in APOE4 homozygotes
APOE2 provides neuroprotection through[3]:
LX1001 represents a groundbreaking approach as the first gene therapy to directly address the APOE4 genetic risk factor in AD:
| Aspect | LX1001 Gene Therapy | Anti-Amyloid Antibodies (Aduhelm, Leqembi) |
|---|---|---|
| Target | APOE4 isoform conversion | Amyloid-beta plaques |
| Mechanism | Genetic (upstream) | Immunological (downstream) |
| Duration | Persistent (multi-year) | Periodic (monthly infusions) |
| Population | APOE4 homozygotes only | Broad AD population |
| Route | Single intrathecal injection | Monthly IV infusion |
| Side effects | Intrathecal procedure risks | ARIA (amyloid-related imaging abnormalities) |
The success of NCT03634007 supports continued development of LX1001:
Participants completing this study are enrolled in NCT05400330, tracking:
APOE genotypes modulate Alzheimer's disease beta-amyloid deposition. JAMA Neurology. 2011. ↩︎
AAVrh.10 serotype for CNS gene therapy. Human Gene Therapy. 2017. ↩︎
APOE2 neuroprotective mechanisms and gene therapy potential. Neurobiology of Disease. 2023. ↩︎