Gene Therapy for Alzheimer's Disease

No longer recruiting at 4 trial locations

Overseen By Lexeo Clinical Trials

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: Lexeo Therapeutics

Must not be taking: Immunosuppressants, Corticosteroids, Anti-amyloid, Anticoagulants

Disqualifiers: Malignancy, Heart failure, Liver failure, others

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

Compensation: Varies

Number of Visits: Unknown

Duration: 52 weeks

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores gene therapy as a treatment for Alzheimer's disease. It specifically targets individuals with two copies of the APOE4 gene who have mild cognitive impairment or mild to moderate dementia due to Alzheimer's. The study tests different doses of the gene therapy LX1001 to determine the most effective and safe amount. Suitable participants must have confirmed Alzheimer's biomarkers and no active infections. As a Phase 1/Phase 2 trial, this research aims to understand how the treatment works in people and measure its effectiveness in an initial, smaller group, offering participants a chance to contribute to groundbreaking Alzheimer's research.

Will I have to stop taking my current medications?

The trial requires that you stop taking certain medications, such as systemic immunosuppressants, corticosteroids, monoclonal anti-amyloid therapies, and anti-coagulant medications. If you are on these medications, you may need to stop them before participating.

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 safe. Earlier studies found LX1001 to be safe and well-tolerated by participants. Importantly, no reports of brain swelling or bleeding occurred, which can sometimes happen with similar treatments. The therapy increased levels of a protein called APOE2, associated with better brain health in Alzheimer's patients. This gene therapy has been tested in varying doses, and so far, no major safety concerns have arisen. ^{1 2 3 4 5}

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

Unlike the standard of care for Alzheimer's disease, which often focuses on managing symptoms with medications like donepezil or memantine, LX1001 is a gene therapy offering a novel approach. LX1001 works by delivering genetic material directly into the cerebrospinal fluid (CSF), potentially allowing for a more targeted intervention in the disease's progression. Researchers are excited about LX1001 because it aims to address the underlying causes of Alzheimer's rather than just alleviating symptoms. Additionally, with varying dosing strategies across its treatment arms, LX1001 allows for a flexible approach to finding the most effective dosage, which could lead to more personalized treatment options.

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

Research has shown that LX1001, a gene therapy, can increase a protein called APOE2, which may help reduce harmful brain changes linked to Alzheimer's disease. In some studies, LX1001 improved tau biomarkers, important for managing Alzheimer's. The treatment is considered safe and has not caused serious side effects like amyloid-related imaging abnormalities. In animal studies, a version of this treatment addressed brain changes seen in Alzheimer's. These findings suggest LX1001 could be promising for treating Alzheimer's symptoms in people with certain genetic backgrounds. Participants in this trial will receive different dosages of LX1001 across various treatment arms to evaluate its effectiveness and safety. ^{1 3 4 6 7}

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 APOE4 homozygotes with mild to moderate Alzheimer's-related cognitive impairment or dementia, who can consent and agree not to share study details on social media. Participants should not be on experimental meds or have active infections like hepatitis or HIV, and must avoid pregnancy during the study.

Inclusion Criteria

Participants who agree not to post their personal data related to the study on social media.

I have been diagnosed with early or moderate Alzheimer's disease.

I haven't taken part in any experimental drug trials for the last 4 weeks.

Exclusion Criteria

I have no allergies to the study drug or related medications.

Prior or concurrent participation in any gene and/or cell therapy

More than 4 cerebral microhemorrhages (regardless of their anatomical location or diagnostic characterization as 'possible' or 'definite'), a single area of superficial siderosis, or evidence of a prior macro hemorrhage on screening MRI

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive intrathecal administration of AAVrh.10hAPOE2 (LX1001) to assess safety and toxicity

52 weeks

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• LX1001

Trial Overview The trial tests LX1001 gene therapy in an open label, dose-ranging format for those diagnosed with varying stages of Alzheimer's disease due to APOE4 homogeneity. It aims to assess its safety and effectiveness in improving cognitive functions.

How Is the Trial Designed?

Group I: Cohort 4: 1.4 x 10^14 gc (fixed dose) Experimental Treatment 1 Intervention

Participants will receive 1.4 x 10\^14 gc (fixed dose; approximately 3.4 × 10\^11 gc/mL CSF based on an average CSF volume of 409 mL) of LX1001.

Group II: Cohort 3: 1.4 x 10^11 gc/mL CSF Experimental Treatment 1 Intervention

Participants will receive 1.4 x 10\^11 gc/mL CSF of LX1001.

Group III: Cohort 2: 4.4 x 10^10 gc/mL CSF Experimental Treatment 1 Intervention

Participants will receive 4.4 x 10\^10 gc/mL CSF of LX1001.

Group IV: Cohort 1: 1.4 x 10^10 gc/mL CSF Experimental Treatment 1 Intervention

Participants will receive 1.4 x 10\^10 gc/mL CSF of LX1001.

Who Is Running the Clinical Trial?

Lexeo Therapeutics

Lead Sponsor

Trials

5

Recruited

110+

Alzheimer's Drug Discovery Foundation

Collaborator

Trials

22

Recruited

3,100+

Weill Medical College of Cornell University

Collaborator

Trials

1,103

Recruited

1,157,000+

Published Research Related to This Trial

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]

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]

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]

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]

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]

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]

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]

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 ... To assess the CNS distribution and safety of APOE2 gene therapy for AD in a large-animal model, intraparenchymal, intracisternal, and intraventricular routes of ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S1525001624007305

AAVrh.10 delivery of novel APOE2-Christchurch variant ... The novel E2 variant E2Ch more effectively treats both the amyloid and tau pathology of murine AD in APOE4 background, supporting the development of AAVrh.10 ...

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 ...

7. trialx.com trialx.com/clinical-trials/listings/271659/long-term-follow-up-of-gene-therapy-for-apoe4-homozygote-alzheimers-disease/

Long-Term Follow-up of Gene Therapy for APOE4 ... This is a long-term follow-up study to evaluate the safety following LX1001, a gene therapy, for participants who are APOE4 homozygotes with ...