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A Clinical Trial of AAV2-BDNF Gene Therapy in Early Alzheimer's Disease and Mild Cognitive Impairment

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ClinicalTrials.gov Identifier: NCT05040217
Recruitment Status : Recruiting
First Posted : September 10, 2021
Last Update Posted : September 10, 2021
Sponsor:
Collaborators:
Case Western Reserve University
Ohio State University
Information provided by (Responsible Party):
Mark Tuszynski, University of California, San Diego

Brief Summary:
This is a first-in-human clinical trial to test whether a protein administered into the brain continuously by gene therapy, Brain-Derived Neurotrophic Factor (BDNF), will slow or prevent cell loss in the brains of people affected by Alzheimer's disease and Mild Cognitive Impairment. The protein may also activate cells in the brain that have not yet deteriorated. Gene therapy refers to the use of a harmless virus to have brain cells make the potentially protective protein, BDNF.

Condition or disease Intervention/treatment Phase
Alzheimer's Disease Genetic: AAV2-BDNF Gene Therapy Biological: AAV2-BDNF Gene Therapy Phase 1

Detailed Description:

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 12 participants.

BDNF is a nervous system growth factor that regulates neuronal function in key memory circuits of the brain (the entorhinal cortex and hippocampus). BDNF reduces cell loss, stimulates cell function, and builds new connections (synapses) between brain cells in animal models.

This clinical trial will use techniques of gene therapy because the candidate therapeutic protein, BDNF, does not cross the blood brain barrier (BBB). Two previous clinical programs of Nerve Growth Factor (NGF) gene therapy for AD and Neurturin gene therapy for Parkinson's disease in over 120 patients provided evidence that degenerating neurons respond to growth factors with classic "trophic" responses in the human brain.

Participants will undergo one gene transfer procedure. Thus, dosing is performed only once, and repeat dosing or daily medications are not expected to be required.

12 participants will be enrolled in this Phase I trial, 6 with early AD and 6 with MCI.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: This study aims to reduce neuronal loss and rebuild synapses in the brain of patients with Alzheimer's Disease (AD) and Mild Cognitive Impairment (MCI). A total of 12 subjects will be enrolled: subjects 1-6 will have a diagnosis of AD and subjects 7-12 will have a diagnosis of MCI. The gene therapy vector will consist of adeno-associated virus serotype 2 (AAV2) and will be stereotaxically administered into the brain under MRI guidance. Subjects will be followed over a pre-determined study time duration of 24 months, and indefinitely thereafter.
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study to Assess the Safety, Tolerability and Preliminary Efficacy of AAV2-BDNF [Adeno-Associated Virus (AAV)-Based, Vector-Mediated Delivery of Human Brain Derived Neurotrophic Factor] in Subjects With Early Alzheimer's Disease and Mild Cognitive Impairment
Actual Study Start Date : March 1, 2021
Estimated Primary Completion Date : March 1, 2023
Estimated Study Completion Date : March 1, 2025


Arm Intervention/treatment
Experimental: Gene transfer of AAV2-BDNF
Up to 12 subjects will receive open-label AAV2-BDNF
Genetic: AAV2-BDNF Gene Therapy
AAV2-BDNF is a genetically engineered adeno-associated virus serotype 2 (AAV-2) that expresses the human BDNF cDNA.

Biological: AAV2-BDNF Gene Therapy
Gene therapy is a biological therapy delivering the BDNF gene to the brain
Other Name: Growth Factor Gene Therapy




Primary Outcome Measures :
  1. Safety as assessed by mumber of participants with treatment-related adverse events assessed on MRI scan [ Time Frame: 24 months ]
    Number of participants with treatment-related adverse events assessed on MRI scan

  2. Memory change tested on Ray Auditory Verbal Learning Task [ Time Frame: 24 months ]
    Memory tested on Ray Auditory Verbal Learning Task

  3. Memory change tested on Benson Complex Figure Draw and Memory [ Time Frame: 24 months ]
    Memory tested on Benson Complex Figure Draw and Memory


Secondary Outcome Measures :
  1. Efficacy on PET scan reflected by change in fluorodeoxyglucose (FDG) PET scan [ Time Frame: 24 months ]
    FDG PET scan

  2. Change in Biomarkers including CSF amyloid, tau and neurofilament [ Time Frame: 24 months ]
    CSF studies of amyloid, tau and neurofilament

  3. Memory change tested on mini-mental status examination (MMSE) [ Time Frame: 24 months ]
    MMSE

  4. Memory tested on Alzheimer's Disease Assessment Scale, Cognitive component (ADAS-Cog) [ Time Frame: 24 months ]
    ADAS-Cog



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Ages Eligible for Study:   50 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • diagnosis of probable Alzheimer's Disease (AD) within 3 years of memory loss
  • diagnosis of Mild Cognitive Impairment
  • age between 50-80 years
  • resident of San Diego or Orange Counties in California, or Ohio.
  • primary language English with no aphasia (no communication impairment)

Exclusion Criteria:

• seizure disorder


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT05040217


Contacts
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Contact: Lori Graham 858-822-3372 ljgraham@ucsd.edu
Contact: Michelle Magana Mendoza 858-822-7438 mmaganamendoza@ucsd.edu

Locations
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United States, California
University of California - San Diego Recruiting
San Diego, California, United States, 92093-0626
Contact: Lori Graham, B.S.    858-822-3372    ljgraham@ucsd.edu   
Contact: Mark Tuszynski, MD, PhD    858-534-8857 ext Tuszynski    mtuszynski@ucsd.edu   
Principal Investigator: Mark Tuszynski, MD, PhD         
Principal Investigator: Gabriel Leger, MD         
United States, Ohio
Case Western Reserve University Not yet recruiting
Cleveland, Ohio, United States, 44106
Contact: Parianne Fatica, B.S.    216-464-6474    Parianne.Fatica@UHhospitals.org   
Principal Investigator: Alan Lerner, MD         
Sponsors and Collaborators
Mark Tuszynski
Case Western Reserve University
Ohio State University
Investigators
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Principal Investigator: Mark Tuszynski, M.D., Ph.D. University of California, San Diego
Publications of Results:
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Responsible Party: Mark Tuszynski, Professor, University of California, San Diego
ClinicalTrials.gov Identifier: NCT05040217    
Other Study ID Numbers: UCSD-BDNF1
First Posted: September 10, 2021    Key Record Dates
Last Update Posted: September 10, 2021
Last Verified: September 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by Mark Tuszynski, University of California, San Diego:
Mild Cognitive Impairment
Additional relevant MeSH terms:
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Alzheimer Disease
Cognitive Dysfunction
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Neurocognitive Disorders
Mental Disorders
Cognition Disorders
Mitogens
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action