Gene Therapy for Alzheimer's Disease

(LEADLTFU Trial)

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

10 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial is a study to evaluate the safety of a gene therapy (LX1001) for people with a specific genetic risk for Alzheimer's disease. The therapy aims to convert a harmful gene variant to a protective one, potentially slowing the disease's progression.

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.

What safety data exists for the gene therapy treatment LX1001/AAVrh.10hAPOE2 for Alzheimer's Disease?

The safety data for the gene therapy treatment AAVrh.10hAPOE2, also known as LX1001, was evaluated in a study using nonhuman primates. The study assessed different routes of delivery to the central nervous system (CNS) and found that intracisternal delivery safely mediated wide distribution of ApoE2 with the least invasive surgical intervention. Conventional toxicology assays were used to assess safety, and the results demonstrated that this method of delivery was safe, providing an optimal strategy for delivering the gene therapy to the CNS. ^{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 without invasive surgery. ^{1 2 3 4 5}

Is the treatment LX1001 a promising treatment for Alzheimer's disease?

Yes, LX1001, also known as AAVrh.10hAPOE2, is a promising treatment for Alzheimer's disease. It aims to protect the brain by introducing a 'protective' gene variant, APOE2, which can help prevent or reverse brain damage associated with Alzheimer's. This treatment has shown potential in safely delivering the gene to the brain, which could help reduce the risk of developing Alzheimer's in people with a higher genetic risk. ^{1 2 3 6 7}

What makes the treatment LX1001 unique for Alzheimer's disease?

LX1001 is a gene therapy that uses a virus to deliver a protective version of a gene called APOE2 directly into the brain, which is different from other treatments that typically target symptoms or amyloid plaques. This approach aims to modify the genetic risk factors associated with Alzheimer's disease, potentially preventing or reversing neurological damage. ^{1 2 3 6 7}

What data supports the idea that Gene Therapy for Alzheimer's Disease (also known as: LX1001, LX1001, AAVrh.10hAPOE2) is an effective treatment?

The available research shows that gene therapy can be effective in treating Alzheimer's Disease by targeting specific genetic mutations. For example, one study demonstrated that delivering a normal version of a gene into the brain of mice with a mutation linked to Alzheimer's helped restore normal enzyme function and slow brain degeneration. Another study showed that using a virus to deliver a small antibody into the brain reduced harmful protein buildup and improved memory in mice. These findings suggest that gene therapy can address the underlying causes of Alzheimer's and improve symptoms, making it a promising treatment option compared to other methods that may only address symptoms without targeting the root cause. ^{2 3 5 8 9}

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

Research on similar gene therapies using adeno-associated virus (AAV) vectors shows promise in treating Alzheimer's disease by delivering therapeutic genes directly to the brain. For example, studies have demonstrated that AAV-mediated delivery can reduce harmful proteins and improve brain function in animal models of Alzheimer's disease. ^{2 3 5 8 9}

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

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]

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]

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]

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]

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]

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]

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]

Citations

1. England pubmed.ncbi.nlm.nih.gov

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

2. 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]

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

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

4. 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]

5. 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]

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

AAV1/2-mediated CNS gene delivery of dominant-negative CCL2 mutant suppresses gliosis, beta-amyloidosis, and learning impairment of APP/PS1 mice. [2021]

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

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