Gene Therapy for Alzheimer's Disease

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

15 Participants Needed

Trial Summary

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.

What data supports the effectiveness of the treatment LX1001, AAVrh.10hAPOE2 for Alzheimer's disease?

Research shows that similar gene therapy approaches using adeno-associated virus (AAV) vectors have been effective in delivering therapeutic genes to the brain, improving symptoms in Alzheimer's disease models. For example, AAV-mediated delivery of therapeutic agents has been shown to reduce amyloid plaques and improve cognitive function in animal models. ^{1 2 3 4 5}

Is the gene therapy treatment AAVrh.10hAPOE2 safe for humans?

In studies with nonhuman primates, the AAVrh.10hAPOE2 gene therapy was found to be safe when delivered to the central nervous system, showing wide distribution with minimal surgical intervention. ^{1 3 5 6 7}

How is the treatment LX1001 unique for Alzheimer's disease?

LX1001 is a gene therapy that uses a virus to deliver a protective gene variant, APOE2, directly into the brain, which is different from most Alzheimer's treatments that focus on reducing amyloid plaques or inflammation. This approach aims to modify genetic risk factors and potentially prevent or reverse neurological damage in patients with a high-risk APOE4 gene variant. ^{3 5 6 8 9}

What is the purpose of this trial?

This trial tests a gene therapy injected into brain fluid for Alzheimer's patients with two APOE4 genes. The therapy aims to change a harmful brain protein to a less harmful version, potentially improving symptoms. Gene therapy is rapidly emerging as a powerful therapeutic strategy for a wide range of neurodegenerative disorders, including Alzheimer's disease.

Research Team

Lexeo Clinical Trials

Principal Investigator

Lexeo Therapeutics

Eligibility Criteria

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

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

Treatment Details

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.

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

References

1. United States pubmed.ncbi.nlm.nih.gov

Developing a Gene Therapy for the Treatment of Autosomal Dominant Alzheimer's Disease. [2023]

2. Netherlands pubmed.ncbi.nlm.nih.gov

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease. [2020]

3. England pubmed.ncbi.nlm.nih.gov

AAV-mediated delivery of an anti-BACE1 VHH alleviates pathology in an Alzheimer's disease model. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Brain-wide Cas9-mediated cleavage of a gene causing familial Alzheimer's disease alleviates amyloid-related pathologies in mice. [2023]

5. England 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. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease. [2019]

7. Netherlands 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. [2010]

8. United States pubmed.ncbi.nlm.nih.gov

Catalytic immunoglobulin gene delivery in a mouse model of Alzheimer's disease: prophylactic and therapeutic applications. [2021]

9. United States 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. [2021]