Gene Therapy for Alzheimer's Disease

(LEADLTFU Trial)

Not currently recruiting at 3 trial locations

Overseen By Lexeo Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1

Sponsor: Lexeo Therapeutics

Disqualifiers: Significant medical condition, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: Unknown

Duration: Not applicable in this follow-up study

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial examines the long-term safety of a gene therapy treatment for Alzheimer's disease. The treatment, LX1001 (also known as AAVrh.10hAPOE2), aims to alter certain genes to improve brain function and reduce Alzheimer's symptoms. It targets individuals with a specific genetic profile (APOE4) who received this treatment in an earlier study. Participants should have mild cognitive issues or dementia due to Alzheimer's and have previously undergone the initial gene therapy. As a Phase 1 trial, the research focuses on understanding how the treatment works in people, offering participants the opportunity to be among the first to receive this innovative therapy.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It's best to discuss this with the study team or your doctor.

Is there any evidence suggesting that this treatment is likely to be safe for humans?

Research has shown that LX1001, a gene therapy for Alzheimer's, is generally safe and well-tolerated. Earlier studies found no serious side effects and reported no cases of ARIA, a condition involving brain swelling or bleeding. Patients showed improvements in protein levels related to Alzheimer's, with greater effects at higher doses. This suggests that the treatment is not only safe but also potentially effective in addressing disease markers. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for Alzheimer's?

Most treatments for Alzheimer's disease focus on managing symptoms or slowing progression through medications like cholinesterase inhibitors and NMDA receptor antagonists. However, LX1001 is unique because it leverages gene therapy to potentially alter the disease's course itself. Researchers are excited about LX1001 because it targets the APOE4 gene, a major genetic risk factor for Alzheimer's, aiming to modify its expression and thereby reduce the risk or severity of the disease. This innovative approach offers a new mechanism of action that could lead to more effective and long-lasting outcomes compared to current treatment options.

What evidence suggests that this gene therapy could be an effective treatment for Alzheimer's disease?

Research shows that LX1001, a gene therapy, increases levels of a protein called APOE2 in a dose-dependent manner. This is significant because APOE2 may help protect against Alzheimer's disease. In earlier studies, patients showed improvements in certain proteins linked to Alzheimer's progression. The treatment proved safe and well-tolerated, with no cases of amyloid-related imaging abnormalities (ARIA), a possible side effect of Alzheimer's treatments. These findings suggest that LX1001 might positively change disease markers for people with Alzheimer's. Participants in this trial will be monitored for up to 260 weeks to evaluate the long-term safety of LX1001. ^{1 2 3 5 6}

Who Is on the Research Team?

Lexeo Clinical Trials

Principal Investigator

Lexeo Therapeutics

Are You a Good Fit for This Trial?

This trial is for individuals with Alzheimer's who have the APOE4 gene variant and previously received LX1001 gene therapy. They must not have any medical conditions that could increase risk during the study, and they agree to keep their personal medical data off social media until all related studies are complete.

Inclusion Criteria

Participants who received LX1001 in study LX1001-01

Exclusion Criteria

Participants who agree not to post their personal medical data in relation to this study or any study information online, including social media sites, until all participants have completed all LX1001 clinical studies, including long-term follow-up.

Participants with any clinically significant medical condition that, in the opinion of the investigator, would pose a risk to participant safety

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants received gene therapy (LX1001) in the parent study LX1001-01

Not applicable in this follow-up study

Follow-up

Participants are monitored for safety and effectiveness after gene therapy

260 weeks

What Are the Treatments Tested in This Trial?

Interventions

• LX1001

Trial Overview

The study is monitoring long-term safety of LX1001 gene therapy in treating Alzheimer's. It also looks at changes in brain markers like amyloid levels, tau proteins, and MRI scans to see if there's improvement in cognitive functions over time.

How Is the Trial Designed?

Group I: Previously administered LX1001 Experimental Treatment 1 Intervention

This is a long-term follow-up study to evaluate the safety following LX1001, a gene therapy, for participants who are APOE4 homozygotes with clinical diagnoses varying from MCI or dementia due to AD who have previously received LX1001. Study LX1001-01 was designed to assess the safety of LX1001 at 4 ascending doses (1.4 × 1010, 4.4 × 1010, 1.4 × 1011 gene copy \[gc\]/mL CSF and 1.4 x 1014 \[fixed dose\]) as per droplet digital polymerase chain reaction methodology, with each group consisting of approximately n=3-5 individuals for a total of approximately 15 participants for the entire study. In this study, participants who have received LX1001 in the parent protocol (LX1001-01) will be followed for up to 260 weeks post gene therapy administration

Who Is Running the Clinical Trial?

Lexeo Therapeutics

Lead Sponsor

Trials

5

Recruited

110+

Published Research Related to This Trial

Aβ-specific catalytic antibodies, like IgVL5D3, can effectively reduce amyloid beta-peptide levels in the brains of Alzheimer's disease model mice without causing harmful side effects such as brain inflammation or hemorrhages.

Using a single injection of a gene delivery system (rAAV9) to introduce IgVL5D3 resulted in widespread expression of the antibody in the brain, demonstrating both prophylactic and therapeutic potential for treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications. Kou, J., Yang, J., Lim, JE., et al.[2021]

The developed siRNA nanocomplex effectively targets amyloid plaques in the brains of APP/PS1 transgenic mice, leading to significant reductions in BACE1 levels and amyloid plaque accumulation, comparable to wild-type mice.

This targeted gene therapy not only improved the biochemical markers of Alzheimer's disease but also rescued memory loss in the mice without causing any harmful side effects, indicating its potential as a safe and effective treatment for AD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease. Guo, Q., Zheng, X., Yang, P., et al.[2020]

A novel gene transfer strategy using BBB-crossing AAV vectors successfully delivered single domain antibodies (VHHs) into the central nervous system, demonstrating potential for treating neurological disorders.

In a mouse model of Alzheimer's disease, a single dose of AAV-VHH-B9 significantly reduced BACE1 activity and led to long-term improvements in amyloid load, neuroinflammation, synaptic function, and cognitive performance over 12 months.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model. Marino, M., Zhou, L., Rincon, MY., et al.[2022]

In a study using nonhuman primates, the intracisternal delivery of a gene therapy vector (AAVrh.10hAPOE2-HA) was found to safely and effectively distribute the protective APOE2 variant throughout the central nervous system, which could potentially reverse or prevent Alzheimer's disease progression.

All three tested delivery methods (intraparenchymal, intracisternal, and intraventricular) were capable of expressing APOE2, but the intracisternal route was the least invasive and provided the best distribution, making it the optimal choice for future therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. Rosenberg, JB., Kaplitt, MG., De, BP., et al.[2019]

Using a hybrid adeno-associated virus (AAV1/2) to deliver a dominant-negative CCL2 mutant gene significantly reduced neuroinflammation and amyloid-beta accumulation in a mouse model of Alzheimer's disease, demonstrating its potential as a therapeutic approach.

The treatment not only decreased the presence of harmful amyloid plaques but also improved spatial learning in the mice, suggesting that targeting CCL2 could be an effective strategy for alleviating symptoms of Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice. Kiyota, T., Yamamoto, M., Schroder, B., et al.[2021]

Intramuscular delivery of an anti-beta-amyloid (Aβ) single chain antibody (scFv) gene in APP(Swe)/PS1dE9 transgenic mice effectively prevented brain Aβ deposition and associated cognitive impairments without causing inflammation or other adverse effects.

The study demonstrated that this method of gene delivery is safe and well-tolerated, suggesting it could be a promising non-inflammatory approach for preventing and treating Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intramuscular delivery of a single chain antibody gene prevents brain Aβ deposition and cognitive impairment in a mouse model of Alzheimer's disease. Wang, YJ., Gao, CY., Yang, M., et al.[2010]

A gene therapy vector delivering a wild-type copy of the PSEN1 gene has been developed, showing promise in normalizing γ-secretase function and slowing neurodegeneration in mouse models of autosomal dominant Alzheimer's disease (ADAD).

Biodistribution studies in nonhuman primates demonstrated broad expression of the PS1 protein in critical brain regions, suggesting that this approach could be effective in clinical settings for treating ADAD.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease. Moore, B., Sharma, A., Goulet, M., et al.[2023]

A single treatment using a CRISPR-Cas9 system to disrupt a mutated APP gene in transgenic mice significantly reduced amyloid-beta-related pathologies for at least six months, suggesting a long-lasting effect on Alzheimer's disease progression.

The study demonstrated that delivering the CRISPR-Cas9 construct intravenously can effectively target and ameliorate multiple symptoms of Alzheimer's, including amyloid-beta deposition and cognitive impairment, indicating a promising approach for treating familial Alzheimer's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer's disease alleviates amyloid-related pathologies in mice. Duan, Y., Ye, T., Qu, Z., et al.[2023]

Adeno-associated virus (AAV) serotype 2/1 hybrid was used to deliver the mouse IL-10 gene to neurons, which improved cognitive function in a mouse model of Alzheimer's disease by reducing neuroinflammation and enhancing neurogenesis.

The study demonstrated that IL-10 gene delivery led to sustained expression of IL-10 in the brain, improved spatial learning, and increased proliferation of neural stem cells, suggesting a promising therapeutic approach for Alzheimer's disease that does not directly target amyloid-β.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV serotype 2/1-mediated gene delivery of anti-inflammatory interleukin-10 enhances neurogenesis and cognitive function in APP+PS1 mice. Kiyota, T., Ingraham, KL., Swan, RJ., et al.[2021]

Citations

1.

ir.lexeotx.com

ir.lexeotx.com/news-releases/news-release-details/lexeo-therapeutics-announces-positive-interim-data-lx1001-first

Press Release

Treatment with LX1001 led to dose-dependent increases in APOE2 protein expression and improvements in AD-associated tau biomarkers.

2.

neurologylive.com

neurologylive.com/view/alzheimer-gene-therapy-lx1001-demonstrates-dose-dependent-increase-apoe2-expression

Alzheimer Gene Therapy LX1001 Demonstrates Dose ...

LX1001, an AAV gene therapy, was considered safe and well tolerated, with no events of amyloid-related imaging abnormalities (ARIA) observed.

3.

clinicaltrials.gov

clinicaltrials.gov/study/NCT05400330

NCT05400330 | Long-Term Follow-up of Gene Therapy for ...

This is a long-term follow-up study to evaluate the safety following LX1001, a gene therapy, for participants who are APOE4 homozygotes with clinical diagnoses ...

4.

pmc.ncbi.nlm.nih.gov

pmc.ncbi.nlm.nih.gov/articles/PMC5870071/

AAVrh.10-Mediated APOE2 Central Nervous System Gene ...

As the next step in moving APOE2 gene therapy for AD to the clinic, the focus of the present study was to determine the most effective safe route of the AAVrh.

5.

cgtlive.com

cgtlive.com/view/gene-therapy-apoe4-homozygous-alzheimer-disease

Gene Therapy for APOE4 Homozygous Alzheimer Disease

Lexeo Therapeutics' LX1001 gene therapy trial that demonstrated promising safety and biomarker effects in patients with early-stage Alzheimer disease.

6.

clinicaltrials.gov

clinicaltrials.gov/study/NCT03634007

NCT03634007 | Gene Therapy for APOE4 Homozygote of ...

The study will assess the safety and toxicity of intrathecal administration of AAVrh.10hAPOE2 (LX1001), serotype rh.10 adeno-associated virus (AAV) gene ...