Background

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. A separate study also reported reduced Aβ plaque deposition, neurodegenerative synaptic loss, and microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4 (Jackson et al., 2024).

Other researchers reported that gene therapy using liposome-based delivery of ApoE2 plasmids to mouse brain reduced levels of insoluble Aβ, but increased soluble oligomers, enhanced neurite dystrophy, and decreased synaptic protein levels (Wang et al., 2024).

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).

Lexeo has two additional gene therapy candidates in preclinical development. LX1021 expresses ApoE2 with the protective Christchurch mutation (Günaydin et al., 2024). LX1020 combines APOE2 expression with microRNA-mediated suppression of APOE4.

Findings

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 called for a single intrathecal injection of one of three doses of LX1001, ranging from 5.7 X 10¹² to 5.7 x 10¹³ gene copies, with a one-year follow-up. Its goals were to establish the maximum tolerable dose, and to 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. In 2023, the study added a fourth dose of 1.4 X 1014 genomes, but did not increase enrollment. The trial was 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. The study finished in November 2024. One-year results of the first three cohorts, and six-month data of the highest dose, were presented at CTAD that year (Nov 2024 news). On safety measures, twelve of the 15 participants developed transiently elevated white blood cells in CSF. A serious adverse event of persistent mild hearing loss was attributed to drug. No ARIA was reported. CSF ApoE2, and the ApoE2/ApoE4 ratio was increased dose-dependently and persistently in all participants. ApoE4 levels did not change at the lower doses, but rose at the highest dose. CSF p-Tau181 and total tau were reduced in most participants after treatment. P-Tau217 and p-Tau231 dropped in four of six participants where it was measured. In PET studies, amyloid accumulation did not change, while tau deposition was possibly stabilized or decreased. An outlier with the highest CSF ApoE2 expression showed the greatest tau-PET reduction at six months.

For details on LX1001 trials, see clinicaltrials.gov.