AAV2-BDNF Gene Therapy for Alzheimer's Disease

Recruiting at 3 trial locations

Overseen By Doug Scharre, MD

Age: 18+

Sex: Any

Trial Phase: Phase 1

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

Approved in 1 Jurisdiction This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

12 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new gene therapy designed to help people with Alzheimer's disease or Mild Cognitive Impairment (MCI). The treatment, AAV2-BDNF Gene Therapy, uses a harmless virus to deliver the protein BDNF directly into the brain to determine if it can protect brain cells and potentially activate those not yet deteriorated. Individuals with a confirmed diagnosis of Alzheimer's or MCI, who have been stable on their medications and have a caregiver available, might be suitable candidates. 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.

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.

Is there any evidence suggesting that AAV2-BDNF Gene Therapy is likely to be safe for humans?

Research has shown that AAV2-BDNF gene therapy could benefit Alzheimer's disease. Early results suggest it might improve memory and brain function. Importantly, initial studies indicate patients tolerate it well, with few side effects reported, suggesting it is safe so far. This therapy uses a safe virus to deliver a protective protein to brain cells, aiming to slow or stop cell loss. While this is encouraging, remember that this is an early-stage trial. Although safety appears promising, more research is needed to confirm these results. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising?

AAV2-BDNF Gene Therapy is unique because it introduces a new approach to treating Alzheimer's by using gene therapy to deliver brain-derived neurotrophic factor (BDNF) directly to the brain. Unlike current treatments that mainly focus on managing symptoms with medications like cholinesterase inhibitors or NMDA receptor antagonists, this therapy aims to address the disease at a cellular level by promoting neuron survival and function. Researchers are excited about this treatment as it could potentially slow or even reverse the progression of Alzheimer's, offering hope for more effective long-term solutions.

What evidence suggests that AAV2-BDNF Gene Therapy might be an effective treatment for Alzheimer's disease?

Research has shown that AAV2-BDNF gene therapy, which participants in this trial will receive, might help with Alzheimer's disease by delivering a protein called BDNF to the brain. This protein could slow or even reverse memory loss by enhancing brain cell connections and efficiency. Studies have found that this therapy can improve brain activity and has been safe in early tests. The treatment uses a harmless virus to help brain cells produce BDNF, potentially protecting them from dying. These promising results suggest that AAV2-BDNF could offer a new approach to addressing Alzheimer's disease. ^{1 2 3 4 6}

Who Is on the Research Team?

Mark Tuszynski, MD, PhD

Principal Investigator

University of California, San Diego

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• AAV2-BDNF Gene 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.

How Is the Trial Designed?

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

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

AAV2-BDNF Gene Therapy is already approved in United States for the following indications:

Approved in United States as AAV2-BDNF Gene Therapy for:

• Alzheimer's Disease
• Mild Cognitive Impairment

Who Is Running the Clinical Trial?

Mark Tuszynski

Lead Sponsor

Trials

1

Recruited

10+

Case Western Reserve University

Collaborator

Trials

314

Recruited

236,000+

Ohio State University

Collaborator

Trials

891

Recruited

2,659,000+

Published Research Related to This Trial

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]

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 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]

Hybrid viral vectors (AAV2/5) were more effective than AAV2 in delivering genes to a wider range of neurons in the brain, which is important for potential treatments of cognitive impairments like Alzheimer's disease.

Both AAV2 and AAV2/5 provided similar long-term neuroprotection for cholinergic neurons, indicating that while delivery efficiency improved with AAV2/5, the overall neuroprotective effect of NGF gene therapy remains consistent.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

AAV2/5-mediated NGF gene delivery protects septal cholinergic neurons following axotomy. Wu, K., Meyer, EM., Bennett, JA., et al.[2007]

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]

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]

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]

Direct gene delivery of AAV2-glial-derived neurotrophic factor (GDNF) to the brain shows promise for treating Parkinson's disease, with successful transport and expression observed in key brain regions after targeted delivery.

Using real-time image-guided techniques improved the accuracy of gene transfer, which is crucial since previous trials failed due to insufficient coverage of the target area, highlighting the importance of delivery methods in achieving therapeutic efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. Kells, AP., Forsayeth, J., Bankiewicz, KS.[2021]

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]

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]

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This is an open label Phase I clinical trial of AAV2-BDNF gene therapy for early Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI) in ...