AAV2-BDNF Gene Therapy for Alzheimer's Disease
Recruiting in Palo Alto (17 mi)
+3 other locations
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.
12345Is 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.
26789How 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.
123410Eligibility 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.
+15 more
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.
+10 more
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
Participant Groups
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.
1Treatment groups
Experimental Treatment
Group I: Gene transfer of AAV2-BDNFExperimental Treatment1 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
Find a Clinic Near You
Research Locations NearbySelect from list below to view details:
University of California - San DiegoLa Jolla, CA
Case Western Reserve UniversityCleveland, OH
University of California - San DiegoSan Diego, CA
The Ohio State UniversityColumbus, OH
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Who Is Running the Clinical Trial?
Mark TuszynskiLead Sponsor
Case Western Reserve UniversityCollaborator
Ohio State UniversityCollaborator
References
[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]To achieve expression of human brain-derived neurotrophic factor (hBDNF) mediated by recombinant adeno-associated virus (rAAV) and explore the mechanism of its neuroprotective effects in rat neurons against beta-amyloid-induced Alzheimer's disease.
Gene transfer provides a practical means for safe, long-term, targeted delivery of biologically active neurotrophic factor proteins for neurodegenerative diseases. [2018]Efforts to develop neurotrophic factors to restore function and protect dying neurons in chronic neurodegenerative diseases like Alzheimer's (AD) and Parkinson's (PD) have been attempted for decades. Despite abundant data establishing nonclinical proof-of-concept, significant delivery issues have precluded the successful translation of this concept to the clinic. The development of AAV2 viral vectors to deliver therapeutic genes has emerged as a safe and effective means to achieve sustained, long-term, targeted, bioactive protein expression. Thus, it potentially offers a practical means to solve those long-standing delivery/translational issues associated with neurotrophic factors. Data are presented for two AAV2 viral vector constructs expressing one of two different neurotrophic factors: nerve growth factor (NGF) and neurturin (NRTN). One (AAV2-NGF; aka CERE-110) is being developed as a treatment to improve the function and delay further degeneration of cholinergic neurons in the nucleus basalis of Meynert, the degeneration of which has been linked to cognitive deficits in AD. The other (AAV2-NRTN; aka CERE-120) is similarly being developed to treat the degenerating nigrostriatal dopamine neurons and major motor deficits in PD. The data presented here demonstrate: (1) 2-year, targeted, bioactive-protein in monkeys, (2) persistent, bioactive-protein throughout the life-span of the rat, and (3) accurately targeted bioactive-protein in aged rats, with (4) no safety issues or antibodies to the protein detected. They also provide empirical guidance to establish parameters for human dosing and collectively support the idea that gene transfer may overcome key delivery obstacles that have precluded successful translation of neurotrophic factors to the clinic. More specifically, they also enabled the AAV-NGF and AAV-NRTN programs to advance into ongoing multi-center, double-blind clinical trials in AD and PD patients.
Postmortem Analysis in a Clinical Trial of AAV2-NGF Gene Therapy for Alzheimer's Disease Identifies a Need for Improved Vector Delivery. [2021]Nerve growth factor (NGF) gene therapy rescues and stimulates cholinergic neurons, which degenerate in Alzheimer's disease (AD). In a recent clinical trial for AD, intraparenchymal adeno-associated virus serotype 2 (AAV2)-NGF delivery was safe but did not improve cognition. Before concluding that NGF gene therapy is ineffective, it must be shown that AAV2-NGF successfully engaged the target cholinergic neurons of the basal forebrain. In this study, patients with clinically diagnosed early- to middle-stage AD received a total dose of 2 × 1011 vector genomes of AAV2-NGF by stereotactic injection of the nucleus basalis of Meynert. After a mean survival of 4.0 years, AAV2-NGF targeting, spread, and expression were assessed by immunolabeling of NGF and the low-affinity NGF receptor p75 at 15 delivery sites in 3 autopsied patients. NGF gene expression persisted for at least 7 years at sites of AAV2-NGF injection. However, the mean distance of AAV2-NGF spread was only 0.96 ± 0.34 mm. NGF did not directly reach cholinergic neurons at any of the 15 injection sites due to limited spread and inaccurate stereotactic targeting. Because AAV2-NGF did not directly engage the target cholinergic neurons, we cannot conclude that growth factor gene therapy is ineffective for AD. Upcoming clinical trials for AD will utilize real-time magnetic resonance imaging guidance and convection-enhanced delivery to improve the targeting and spread of growth factor gene delivery.
[Construction and expression of recombinant adeno-associated virus expressing brain-derived neurotrophic factor]. [2008]A fusion gene called Ig-BDNF, in which brain-derived neurotrophic factor cDNA fused to the 3' end of signal peptide of Ig coding sequence, was constructed by PCR, digested and subcloned into shuttle plasmid pSNAV to obtain a recombinant plasmid pSNAV-Ig-BDNF. Then the plasmid encoding fusion protein was transfected into 293 cell lines and the stably transfected clones were selected with neomycin. AAV1 containing Ig-BDNF fusion gene vectors were obtained by super-infection by Herpes virus. The resultant adeno-associated virus vectors AAV-Ig-BDNF were confirmed by PCR, Western blotting and a sandwich enzyme-linked immunosorbent assay (ELISA) after infection of 293 cell lines. The results indicated that AAV-Ig-BDNF contained the target gene, and infected cells and produced the fusion protein into the supernatant. The content of BDNF in medium per 5x104 cells over a 24 h incubation period reached 1000 pg/mL. With the help of non-replicative adenovirus during AAV-Ig-BDNF infection, the expression of BDNF increased 7-8 fold, and the enhancement of BDNF gene expression was observed in a concentration-dependent manner. These results suggested that a functional AAV-Ig-BDNF was successfully constructed and it offers basis for further study for gene therapy of neural degeneration diseases.
AAV2/5-mediated NGF gene delivery protects septal cholinergic neurons following axotomy. [2007]Nerve growth factor (NGF) therapy has been proposed to treat cognitive impairments in aged patients including those with Alzheimer's disease. Various viral vectors, including adeno-associated virus serotype 2 (AAV2), have been investigated for their ability to deliver NGF in brain. In this study, hybrid vectors (AAV2/5) consisting of the genome of recombinant AAV2 and the capsid of AAV serotype 5 were evaluated for their ability to deliver NGF and green fluorescent protein (GFP) genes into brain. Compared to AAV2, AAV2/5 consistently led to more septal neurons being transduced with GFP over a wider range of distribution. However, both types of vector provided similar levels of long-term (17 weeks) protection of septal cholinergic neurons from axotomy and led to similar levels of NGF accumulation in this region. These results demonstrate that rAAV-mediated NGF gene delivery is neuroprotective for an extended period of time, but that factors other than transduction efficiency appear to determine transgenic NGF expression in septum.
Plasma BDNF levels associate with Pittsburgh compound B binding in the brain. [2020]Brain-derived neurotrophic factor (BDNF) plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. BDNF function is adversely affected by amyloid beta (Aβ) in AD. BDNF levels in brain and peripheral tissues are lower in patients with AD and MCI, than in controls. Here we examined the association between plasma levels of BDNF and amyloid deposition in the brain measured with Pittsburgh Compound B (PiB).
Establishment of effective methods for transducing genes into iris pigment epithelial cells by using adeno-associated virus type 2. [2018]To establish an efficient method of transferring the human brain-derived neurotrophic-factor (hBDNF) gene into human iris pigment epithelial (hIPE) cells by using recombinant adeno-associated virus type 2 (rAAV2).
Safety Assessment of AAV2-hGDNF Administered Via Intracerebral Injection in Rats for Treatment of Parkinson's Disease. [2022]Glial cell line-derived neurotrophic factor (GDNF) is a potent neuroprotective biologic in Parkinson's disease models. Adeno-associated viral vector serotype 2 (AAV2)-human GDNF safety was assessed in rats treated with a single intracerebral dose of vehicle, 6.8 × 108, 6.8 × 109, or 5.2 × 1010 vector genomes (vg)/dose followed by interim sacrifices on day 7, 31, 90, and 376. There were no treatment-related effects observed on food consumption, body weight, hematology, clinical chemistry, coagulation parameters, neurobehavioral parameters, organ weights, or serum GDNF and anti-GDNF antibody levels. Increased serum anti-AAV2 neutralizing antibody titers were observed in the 5.2 × 1010 vg/dose group. Histopathological lesions were observed at the injection site in the 6.8 × 109 vg/dose (day 7) and 5.2 × 1010 vg/dose groups (days 7 and 31) and consisted of gliosis, mononuclear perivascular cuffing, intranuclear inclusion bodies, and/or apoptosis on day 7 and mononuclear perivascular cuffing on day 31. GDNF immunostaining was observed in the injection site in all dose groups through day 376 indicating no detectable impacts of anti-AAV2 neutralizing antibody. There was no evidence of increased expression of calcitonin gene-related peptide or Swann cell hyperplasia in the cervical and lumbar spinal cord or medulla oblongata at the 5.2 × 1010 vg/dose level indicating lack of hyperplastic effects. In conclusion, no systemic toxicity was observed, and the local toxicity observed at the injection site appeared to be reversible demonstrating a promising safety profile of intracerebral AAV2-GDNF delivery. Furthermore, an intracerebral dose of 6.8 × 108 AAV2-GDNF vg/dose was considered to be a no observed adverse effect level in rats.
Design of a Novel Gene Therapy Construct to Achieve Sustained Brain-Derived Neurotrophic Factor Signaling in Neurons. [2019]Brain-derived neurotrophic factor (BDNF) acting through the tropomyosin-related receptor-B (TrkB) is an important signaling system for the maintenance and survival of neurons. Gene therapy using either recombinant adeno-associated virus (AAV) or lentiviral vectors can provide sustained delivery of BDNF to tissues where reduced BDNF signaling is hypothesized to contribute to disease pathophysiology. However, elevation in BDNF at target sites has been shown to lead to a downregulation of TrkB receptors, thereby reducing the effect of chronic BDNF delivery over time. A novel gene sequence has been designed coding both the ligand (BDNF) and the TrkB receptor in a single transgene separated by a short viral-2A sequence. The single transgene is efficiently processed intracellularly in vitro and in vivo to yield the two mature proteins, which are then independently transported to their final cellular locations: TrkB receptors to the cell surface, and BDNF contained within secretory vesicles. To accommodate the coding sequences of both BDNF and TrkB receptors within the narrow confines of the AAV vectors (4.7 kb pairs), the coding region for the pro-domain of BDNF was removed and the signal peptide sequence modified to improve production, intracellular transport, and secretion of mature BDNF (mBDNF). Intracellular processing and efficacy was shown in HEK293 cells and SH-SY5Y neuroblastoma cells using plasmid DNA and after incorporating the TrkB-2A-mBDNF into an AAV2 vector. Increased BDNF/TrkB-mediated intracellular signaling pathways were observed after AAV2 vector transfection while increased TrkB phosphorylation could be detected in combination with neuroprotection from hydrogen peroxide-induced oxidative stress. Correct processing was also shown in vivo in mouse retinal ganglion cells after AAV2 vector administration to the eye. This novel construct is currently being investigated for its efficacy in animal models to determine its potential to progress to human clinical studies in the future.
Glial-derived neurotrophic factor gene transfer for Parkinson's disease: anterograde distribution of AAV2 vectors in the primate brain. [2021]Delivery of neurotrophic factors to treat neurodegenerative diseases has not been efficacious in clinical trials despite their known potency for promoting neuronal growth and survival. Direct gene delivery to the brain offers an approach for establishing sustained expression of neurotrophic factors but is dependent on accurate surgical procedures to target specific anatomical regions of the brain. Serotype-2 adeno-associated viral (AAV2) vectors have been investigated in multiple clinical studies for neurological diseases without adverse effects; however the absence of significant clinical efficacy after neurotrophic factor gene transfer has been largely attributed to insufficient coverage of the target region. Our pre-clinical development of AAV2-glial-derived neurotrophic factor (GDNF) for Parkinson's disease involved real-time image guided delivery and optimization of delivery techniques to maximize gene transfer in the putamen. We have demonstrated that AAV2 vectors are anterogradely transported in the primate brain with GDNF expression observed in the substantia nigra after putaminal delivery in both intact and nigrostriatal lesioned primates. Direct midbrain delivery of AAV2-GDNF resulted in extensive anterograde transport to multiple brain regions and significant weight loss.