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Name: LX1001
Synonyms: AAVrh.10-APOE2, AAVrh.10hAPOE2
Therapy Type: DNA/RNA-based
Target Type: Amyloid-Related (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Phase 1)
Company: Lexeo Therapeutics


This gene-therapy approach uses a viral vector to drive expression of human apolipoprotein E2 protein (APOE2) in the central nervous system. The serotype rh.10 adeno-associated virus with APOE2 cDNA is surgically injected into the spinal canal so that it reaches the cerebrospinal fluid and brain. 

APOE gene isoforms strongly affect the risk of developing Alzheimer’s disease. APOE4 raises the risk, APOE2 reduces it. APOE4 is associated with acceleration of amyloid accumulation in the brain compared with other isoforms; E2 protects against pathology (e.g., Reiman et al., 2020). The rationale for gene therapy is to increase the expression of E2, and overcome the harmful effects of E4.

In preclinical work, AAVrh.10-APOE2 was tested in mice expressing human APP, PS1, and APOE4. Intracerebral delivery of the virus led to widespread brain expression of APOE2, and decreased Aβ levels and amyloid deposition (Zhao et al., 2016). APOE2 gene therapy reduced amyloid most effectively when given before plaque accumulation began.

Studies using nonhuman primates compared APOE2 expression in brain two months after intraparenchymal, intracisternal, or intraventricular delivery of AAVrh.10-APOE2. Intracisternal delivery was the safest and resulted in widespread brain expression of APOE2 (Rosenberg et al., 2018).


In November 2019, investigators at Weill Medical College of Cornell University began a Phase 1 trial evaluating LX1001 in 15 volunteers who carry two APOE4 alleles and have PET- or CSF-confirmed brain amyloid deposition and a clinical diagnosis of mild cognitive impairment to moderate dementia. This open-label, dose-ranging study involves a single intrathecal injection of one of three doses of LX1001, and a one-year follow-up. Its goals are to establish the maximum tolerable dose and determine if APOE2 protein appears in the cerebrospinal fluid. The primary endpoint is safety and the number of adverse events or serious adverse events one year after injection. Secondary endpoints include change in CSF ApoE isoforms and biomarkers, amyloid PET, volumetric MRI, and cognitive and functional measures. The trial is set to end in April 2024. A five-year follow up to assess safety and biomarkers will run until 2028.

In April 2021, the FDA granted LX1001 Fast-Track designation.  

In March 2022, Lexeo announced top-line results from the lowest-dose group. According to its press release, APOE2 protein was detectable in CSF after three months in all four participants in the cohort, and after one year in the two who reached that time point. In these two, total tau and phosphorylated tau reportedly declined from baseline at one year. The company reported no serious adverse events. At the CTAD 2022 conference, the company presented data from an additional participant, who showed a similar one-year expression of ApoE2 and drops in total tau and phosphorylated tau (Dec 2022 news). No serious adverse events occurred in this group, or in the mid-dose group, who received three times the dose.

For details on this trial, see

Last Updated: 02 Jan 2023


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News Citations

  1. In Small Trial, Gene Therapy Spurs ApoE2 Production

Paper Citations

  1. . Exceptionally low likelihood of Alzheimer's dementia in APOE2 homozygotes from a 5,000-person neuropathological study. Nat Commun. 2020 Feb 3;11(1):667. PubMed.
  2. . Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging. 2016 Aug;44:159-72. Epub 2016 Apr 30 PubMed.
  3. . AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. Hum Gene Ther Clin Dev. 2018 Mar;29(1):24-47. Epub 2018 Mar 13 PubMed.

External Citations

  1. press release

Further Reading


  1. . Therapeutic approaches targeting Apolipoprotein E function in Alzheimer's disease. Mol Neurodegener. 2020 Jan 31;15(1):8. PubMed.
  2. . ApoE-2 Brain-Targeted Gene Therapy Through Transferrin and Penetratin Tagged Liposomal Nanoparticles. Pharm Res. 2019 Sep 16;36(11):161. PubMed.
  3. . Gene transfer of human Apoe isoforms results in differential modulation of amyloid deposition and neurotoxicity in mouse brain. Sci Transl Med. 2013 Nov 20;5(212):212ra161. PubMed.
  4. . Gene delivery of human apolipoprotein E alters brain Abeta burden in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2005 Jan 25;102(4):1211-6. PubMed.