AAV2-BDNF Gene Therapy for Alzheimer's Disease

Recruiting at3 trial locations

Overseen by Mark Tuszynski, MD, PhD

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1

Recruiting

Sponsor: Mark Tuszynski

Must be taking: Anti-cholinesterases, Memantine

Must not be taking: Beta-blockers, Narcotics, Neuroleptics, others

Disqualifiers: Neurological disease, Major depression, Cancer, others

No Placebo Group

Approved in 1 Jurisdiction

Trial Summary

What is the purpose of this trial?

This trial tests a new gene therapy that uses a virus to deliver a protective protein called BDNF into the brains of people with early Alzheimer's Disease and Mild Cognitive Impairment. The goal is to help brain cells survive, function better, and form new connections. The therapy aims to slow or prevent further brain cell loss. Brain-derived neurotrophic factor (BDNF) has been explored for its potential to support neuron survival and function in neurodegenerative diseases.

Will I have to stop taking my current medications?

The trial requires that certain medications be stable for at least one month before screening, such as antidepressants without significant side effects, estrogen-replacement therapy, anti-cholinesterases, and memantine. However, some medications must be stopped before the trial, including certain beta-blockers, narcotics, and anti-Parkinsonian medications, among others. Please review the specific medication list with your doctor to see if any changes are needed.

What data supports the effectiveness of the AAV2-BDNF Gene Therapy treatment for Alzheimer's Disease?

Research shows that using a virus to deliver brain-derived neurotrophic factor (BDNF) can protect neurons in rats from damage similar to that seen in Alzheimer's. Additionally, similar gene therapies using adeno-associated viruses have been shown to safely deliver proteins that protect neurons in other neurodegenerative diseases, suggesting potential for Alzheimer's treatment. ^{1 2 3 4 5}

Is AAV2-BDNF Gene Therapy safe for humans?

Research on similar AAV2-based gene therapies for other conditions, like Parkinson's disease, shows no major safety issues in animal studies, with some local effects at the injection site that were reversible. This suggests a promising safety profile, but specific human safety data for AAV2-BDNF Gene Therapy is not detailed in the available research. ^{2 6 7 8 9}

How is AAV2-BDNF Gene Therapy different from other treatments for Alzheimer's disease?

AAV2-BDNF Gene Therapy is unique because it uses a viral vector to deliver the brain-derived neurotrophic factor (BDNF) gene directly to the brain, aiming for long-term expression of proteins that support neuron health, which is different from traditional treatments that typically involve medications to manage symptoms. ^{1 2 3 4 10}

Research Team

Mark Tuszynski, MD, PhD

Principal Investigator

University of California, San Diego

Eligibility Criteria

This trial is for people aged 50-80 in San Diego, Orange Counties, California or Ohio with early Alzheimer's or Mild Cognitive Impairment. They must speak English without communication issues and have a caregiver. Participants need to be generally healthy, not pregnant, and have stable medication use for at least one month.

Inclusion Criteria

I am 50 years old or older.

Subject is not pregnant, lactating, or of child-bearing potential

I have been diagnosed with Alzheimer's Disease according to NIA-AA criteria.

Exclusion Criteria

I have not been diagnosed with major depression or a significant psychiatric disorder in the last two years.

I have a history of cancer.

I do not have any major neurological conditions.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Gene Transfer Procedure

Participants undergo one gene transfer procedure for AAV2-BDNF

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after the gene transfer procedure

24 months

Regular visits for assessments including MRI, PET scans, and cognitive tests

Treatment Details

Interventions

• AAV2-BDNF Gene Therapy (Virus Therapy)

Trial Overview The trial tests AAV2-BDNF Gene Therapy as a potential treatment for Alzheimer's Disease and Mild Cognitive Impairment. It involves using a harmless virus to deliver BDNF protein into the brain to protect against cell loss and activate remaining cells.

Participant Groups

Group I: Gene transfer of AAV2-BDNF Experimental Treatment 1 Intervention

Up to 12 subjects will receive open-label AAV2-BDNF

Who Is Running the Clinical Trial?

Mark Tuszynski

Lead Sponsor

Trials

1

Recruited

10+

Case Western Reserve University

Collaborator

Trials

314

Recruited

236,000+

Eric W. Kaler

Case Western Reserve University

Chief Executive Officer since 2021

PhD in Chemical Engineering from the University of Minnesota

Stanton L. Gerson

Case Western Reserve University

Chief Medical Officer since 2020

MD from Harvard Medical School

Ohio State University

Collaborator

Trials

891

Recruited

2,659,000+

Dr. John J. Warner

Ohio State University

Chief Executive Officer since 2023

MD, MBA

Dr. Peter Mohler

Ohio State University

Chief Medical Officer since 2023

PhD in Molecular Biology

Findings from Research

The study successfully used a recombinant adeno-associated virus (rAAV) to express human brain-derived neurotrophic factor (hBDNF) in rat hippocampal neurons, demonstrating its potential for neuroprotection against beta-amyloid-induced damage.

hBDNF expression significantly reduced cell apoptosis by increasing Bcl-2 protein levels and maintaining calcium balance in neurons, suggesting a mechanism for its protective effects in Alzheimer's disease models.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Protective effect of adeno-associated viral vector-mediated expression of human brain-derived neurotrophic factor in rat neurons against beta-amyloid-induced Alzheimer's disease in vitro]. Liu, ZH., Ma, DL., Jin, H., et al.[2010]

AAV2 viral vectors have been developed to deliver neurotrophic factors like NGF and NRTN, showing promising results in animal studies with sustained protein expression and no safety issues, paving the way for clinical applications in Alzheimer's and Parkinson's diseases.

These vectors have successfully advanced into multi-center, double-blind clinical trials, indicating their potential to address long-standing delivery challenges associated with neurotrophic factors in treating neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. Herzog, CD., Bishop, KM., Brown, L., et al.[2018]

In a study involving patients with early- to middle-stage Alzheimer's disease, AAV2-NGF gene therapy was found to be safe, with NGF gene expression persisting for at least 7 years at the injection sites, but it did not effectively reach the target cholinergic neurons due to limited spread (only 0.96 mm) and inaccurate targeting.

The study suggests that the lack of cognitive improvement in the clinical trial may not indicate the ineffectiveness of NGF therapy, as future trials will use advanced imaging techniques to enhance targeting and delivery of the therapy to cholinergic neurons.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery. Castle, MJ., Baltanás, FC., Kovacs, I., et al.[2021]

A functional adeno-associated virus (AAV) vector containing the Ig-BDNF fusion gene was successfully constructed, which significantly increased the expression of brain-derived neurotrophic factor (BDNF) in 293 cell lines by 7-8 times, indicating its potential for therapeutic applications.

The study demonstrated that the AAV-Ig-BDNF vector could produce a substantial amount of BDNF (1000 pg/mL) in the culture medium, suggesting its efficacy for future gene therapy targeting neural degeneration diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Construction and expression of recombinant adeno-associated virus expressing brain-derived neurotrophic factor]. Li, H., Qiu, W., Wang, F., et al.[2008]

In a study involving 77 participants (18 with Alzheimer's disease, 56 with mild cognitive impairment, and 3 normal controls), lower plasma levels of brain-derived neurotrophic factor (BDNF) were significantly linked to higher amyloid deposition in the brain, particularly in key regions associated with Alzheimer's disease.

The findings suggest that monitoring plasma BDNF levels could provide insights into the extent of amyloid burden in the brain, potentially aiding in the understanding and management of Alzheimer's disease and related conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Plasma BDNF levels associate with Pittsburgh compound B binding in the brain. Hwang, KS., Lazaris, AS., Eastman, JA., et al.[2020]

The combination of hydroxyurea-sodium butyrate (HUSB) and tyrphostin-1 (Tyr) significantly enhances the expression of the human brain-derived neurotrophic factor (hBDNF) gene in human iris pigment epithelial (hIPE) cells when using recombinant adeno-associated virus type 2 (rAAV2).

BDNF produced from HUSB-Tyr-treated rAAV-hBDNF-hIPE cells showed a greater neuroprotective effect on retinal ganglion cells (RGCs) compared to cells treated with HUSB alone, indicating that this method could be beneficial for retinal health.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Establishment of effective methods for transducing genes into iris pigment epithelial cells by using adeno-associated virus type 2. Sugano, E., Tomita, H., Ishiguro, S., et al.[2018]

The study assessed the safety of AAV2-human GDNF in rats, finding no systemic toxicity and only reversible local toxicity at the injection site, indicating a promising safety profile for this treatment in Parkinson's disease models.

The lowest dose of 6.8 × 108 vector genomes per dose was identified as the no observed adverse effect level, suggesting it may be the safest option for further studies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease. Terse, PS., Kells, AP., Noker, P., et al.[2022]

A novel gene therapy approach has been developed that delivers both brain-derived neurotrophic factor (BDNF) and its receptor TrkB in a single transgene, which may enhance neuronal survival and function by maintaining effective signaling pathways.

This method has shown promising results in vitro and in vivo, including increased TrkB phosphorylation and neuroprotection against oxidative stress, indicating its potential for future clinical applications in treating neurodegenerative diseases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons. Osborne, A., Wang, AXZ., Tassoni, A., et al.[2019]

References

1. China pubmed.ncbi.nlm.nih.gov

[Protective effect of adeno-associated viral vector-mediated expression of human brain-derived neurotrophic factor in rat neurons against beta-amyloid-induced Alzheimer's disease in vitro]. [2010]

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

Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. [2018]

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

Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery. [2021]

4. China pubmed.ncbi.nlm.nih.gov

[Construction and expression of recombinant adeno-associated virus expressing brain-derived neurotrophic factor]. [2008]

5. Netherlands pubmed.ncbi.nlm.nih.gov

AAV2/5-mediated NGF gene delivery protects septal cholinergic neurons following axotomy. [2007]

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

Plasma BDNF levels associate with Pittsburgh compound B binding in the brain. [2020]

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

Establishment of effective methods for transducing genes into iris pigment epithelial cells by using adeno-associated virus type 2. [2018]

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

Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease. [2022]

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

Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons. [2019]

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

Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. [2021]