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

NCT05040217 | Recruiting Phase 1 DMC FDA Drug

• 1 other identifier: UCSD-BDNF1
• Study Type: interventional
• Target: 12
• Locations: 1 country
• Sites: 2

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.

Conditions

Alzheimer's Disease; Mild Cognitive Impairment

Keywords

Mild Cognitive Impairment; Gene Therapy

Outcome Measures

Primary Outcomes (3)

• Safety as assessed by mumber of participants with treatment-related adverse events assessed on MRI scan

  Number of participants with treatment-related adverse events assessed on MRI scan

  24 months

• Memory change tested on Ray Auditory Verbal Learning Task

  Memory tested on Ray Auditory Verbal Learning Task

  24 months

• Memory change tested on Benson Complex Figure Draw and Memory

  Memory tested on Benson Complex Figure Draw and Memory

  24 months

Secondary Outcomes (4)

• Efficacy on PET scan reflected by change in fluorodeoxyglucose (FDG) PET scan

  24 months

• Change in Biomarkers including CSF amyloid, tau and neurofilament

  24 months

• Memory change tested on mini-mental status examination (MMSE)

  24 months

• Memory tested on Alzheimer's Disease Assessment Scale, Cognitive component (ADAS-Cog)

  24 months

Study Arms (1)

Gene transfer of AAV2-BDNF

EXPERIMENTAL

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

Genetic: AAV2-BDNF Gene Therapy; Biological: AAV2-BDNF Gene Therapy

Interventions

AAV2-BDNF Gene Therapy GENETIC

AAV2-BDNF is a genetically engineered adeno-associated virus serotype 2 (AAV-2) that expresses the human BDNF cDNA.

Gene transfer of AAV2-BDNF

Eligibility Criteria

• Age: 50 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Diagnosis of dementia due to Alzheimer's Disease (AD) by National Institute of Aging (NIA) - Alzheimer's Association (AA) criteria for AD 15. The diagnosis of probable AD according to NIA criteria 15 is internationally recognized as the "gold standard" for diagnosing AD.
• Mini-Mental State Exam score between 22 and 28 (inclusive).
• No significant cerebral vascular disease: modified Hachinski score of ≤ 4.
• Age 50 - 80 years old.
• EEG is free of epileptiform abnormalities.
• Permitted medications stable for at least one month prior to screening. In particular:
• Subjects taking stable doses of antidepressants lacking significant anti-cholinergic side effects are acceptable (if they are not currently depressed and do not have a history of major depression within the past two years).
• Estrogen-replacement therapy is permissible.
• Anti-cholinesterases and memantine are allowed (stable doses for preceding 3 months).
• Geriatric Depression Rating scale indicates no depression (Geriatric Depression Scale not greater than 8 on GDS-30).
• A caregiver is available who has frequent contact with the subject (e.g., an average of ten hours/week or more), agrees to observe for adverse events, and will accompany the subject to all clinic visits for the duration of the protocol.
• CT or MRI scans within 24 months prior to screening without evidence of an infection, infarction, or other focal (e.g., subdural hematomas) or generalized lesions (e.g., hydrocephalus) and without clinical symptoms suggestive of intervening neurological disease. A lacune in a non-critical brain area that is not believed to contribute to the cognitive impairment is permissible.
• Adequate visual and auditory acuity to allow neuropsychological testing that requires visual and auditory acuity.
• Good general health with no additional diseases expected to interfere with the study in the opinion of the investigator.
• Normal serum B12, RPR, and thyroid function tests; or clinically insignificant abnormalities that would not be expected to interfere with the study.

You may not qualify if:

• Any significant neurological disease other than suspected incipient disease; i.e., seizure disorder, Parkinson's disease, multi-infarct dementia, Huntington's disease, normal pressure hydrocephalus, brain tumor, progressive supranuclear palsy, subdural hematoma, multiple sclerosis, arteriovenous malformation or history of significant head trauma followed by persistent neurologic deficits or known structural abnormalities.
• Individual has symptoms of aphasia which would make administration of study assessments and collection of information during study challenging.
• Major depression or another major psychiatric disorder as described in DMS-IV within the past two years.
• Psychotic features, agitation or behavioral problems within the last three months which could lead to difficulty in cooperating with study.
• History of alcohol or substance abuse or dependence within the past two years (DMS-IV criteria).
• History of schizophrenia (DMS-IV criteria).
• Affirms suicidal ideation in response to questions number 4 or 5 in the C-SSRS during the past 3 months (i.e., "active suicidal ideation with some intent to act, without specific plan" or "active suicidal ideation with specific plan and intent") or affirms any of the questions contained in the Suicidal Behavior section of the C-SSRS as applicable during the past 12 months.
• History of systemic cancer within the past 18 months (non-metastatic skin cancers are acceptable).
• Any significant systemic illness or unstable medical conditions which could lead to difficulty complying with the protocol including:
• History of myocardial infarction in the past year or unstable or severe cardiovascular disease including angina or congestive heart failure with symptoms at rest.
• Clinically significant obstructive pulmonary disease or asthma.
• Clinically significant and unstable gastrointestinal disorder; i.e., ulcer disease or history of active or occult gastrointestinal bleeding within two years.
• Clinically significant test abnormalities on the battery of screening tests (hematology, prothrombin time, chemistry, urinalysis, ECG).
• Insulin-requiring diabetes or uncontrolled diabetes mellitus.
• Uncontrolled hypertension (systolic blood pressure greater than 180 or diastolic blood pressure greater than 110).

Sponsors & Collaborators

• Mark Tuszynski: lead
• Ohio State University: collaborator

Study Sites (2)

University of California - San Diego

La Jolla, California, 92093, United States

RECRUITING

The Ohio State University

Columbus, Ohio, 43210, United States

RECRUITING

Related Publications (5)

• Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, Wang L, Blesch A, Kim A, Conner JM, Rockenstein E, Chao MV, Koo EH, Geschwind D, Masliah E, Chiba AA, Tuszynski MH. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer's disease. Nat Med. 2009 Mar;15(3):331-7. doi: 10.1038/nm.1912. Epub 2009 Feb 8.

  PMID: 19198615 RESULT

• Nagahara AH, Tuszynski MH. Potential therapeutic uses of BDNF in neurological and psychiatric disorders. Nat Rev Drug Discov. 2011 Mar;10(3):209-19. doi: 10.1038/nrd3366.

  PMID: 21358740 RESULT

• Nagahara AH, Mateling M, Kovacs I, Wang L, Eggert S, Rockenstein E, Koo EH, Masliah E, Tuszynski MH. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci. 2013 Sep 25;33(39):15596-602. doi: 10.1523/JNEUROSCI.5195-12.2013.

  PMID: 24068826 RESULT

• Tuszynski MH, Yang JH, Barba D, U HS, Bakay RA, Pay MM, Masliah E, Conner JM, Kobalka P, Roy S, Nagahara AH. Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurol. 2015 Oct;72(10):1139-47. doi: 10.1001/jamaneurol.2015.1807.

  PMID: 26302439 RESULT

• Tuszynski MH. Growth Factor Gene Therapy for Alzheimer's Disease. J Alzheimers Dis. 2024;101(s1):S433-S441. doi: 10.3233/JAD-240545.

  PMID: 39422960 DERIVED

MeSH Terms

Conditions

Alzheimer Disease; Cognitive Dysfunction

Condition Hierarchy (Ancestors)

Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Cognition Disorders

Study Officials

• Mark Tuszynski, M.D., Ph.D.

  University of California, San Diego

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Andrea Davis, MS

CONTACT

6148146871; andrea.davis@osumc.edu

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Professor

Model Details: 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.

Study Record Dates

• First Submitted: June 21, 2021
• First Posted: September 10, 2021
• Study Start: February 7, 2022
• Primary Completion (Estimated): December 1, 2027
• Study Completion (Estimated): December 1, 2027
• Last Updated: October 21, 2025

Record last verified: 2025-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (2)