Alzheimer's Disease, Mild Cognitive Impairment
Conditions
Keywords
Mild Cognitive Impairment, Gene Therapy
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.
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.
Interventions
GENETICAAV2-BDNF Gene Therapy
AAV2-BDNF is a genetically engineered adeno-associated virus serotype 2 (AAV-2) that expresses the human BDNF cDNA.
Sponsors
Mark Tuszynski
Ohio State University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
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.
Eligibility
Sex/Gender
ALL
Age
50 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
Specific inclusion criteria will be as follows for patients 1-6 (Mild AD dementia): 1. 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. 2. Mini-Mental State Exam score between 22 and 28 (inclusive). 3. No significant cerebral vascular disease: modified Hachinski score of ≤ 4. 4. Age 50 - 80 years old. 5. EEG is free of epileptiform abnormalities. 6. Permitted medications stable for at least one month prior to screening. In particular: 1. 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). 2. Estrogen-replacement therapy is permissible. 3. Anti-cholinesterases and memantine are allowed (stable doses for preceding 3 months). 7. Geriatric Depression Rating scale indicates no depression (Geriatric Depression Scale not greater than 8 on GDS-30). 8. 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. 9. 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. 10. Adequate visual and auditory acuity to allow neuropsychological testing that requires visual and auditory acuity. 11. Good general health with no additional diseases expected to interfere with the study in the opinion of the investigator. 12. Normal serum B12, RPR, and thyroid function tests; or clinically insignificant abnormalities that would not be expected to interfere with the study. 13. ECG without clinically significant abnormalities that would be expected to interfere with the study. 14. Subject is not pregnant, lactating, or of child-bearing potential (i.e., women must be post-menopausal or surgically sterile). Specific inclusion criteria will be as follows for patients 7-12 (MCI due to AD): 1. Diagnosis of Mild Cognitive Impairment (MCI) due to Alzheimer's Disease by NIA-AA criteria 16. The diagnosis of MCI is also internationally recognized as the current standard for diagnosing MCI. 2. Mini-Mental State Exam score between 24 and 29 (inclusive) and examination consistent with diagnosis of MCI. We will not require CSF biomarkers for subclassifying MCI risk of progression to AD. 3. No significant cerebral vascular disease: modified Hachinski score of ≤ 4. 4. Minimum age 50. 5. EEG is free of epileptiform abnormalities. 6. Permitted medications stable for at least one month prior to screening. In particular: 1. 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). 2. Estrogen-replacement therapy is permissible. 3. Anti-cholinesterases and memantine are allowed (stable doses for preceding 3 months). 7. Geriatric Depression Rating scale indicates no depression (Geriatric Depression Scale not greater than 8 on GDS-30). 8. 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. 9. 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. 10. Adequate visual and auditory acuity to allow neuropsychological testing that was a visual and auditory acuity. 11. Good general health with no additional diseases expected to interfere with the study in the opinion of the investigator. 12. Normal serum B12, RPR, and thyroid function tests; or clinically insignificant abnormalities that would not be expected to interfere with the study. 13. ECG without clinically significant abnormalities that would be expected to interfere with the study. 14. Subject is not pregnant, lactating, or of child-bearing potential (i.e., women must be post-menopausal or surgically sterile).
Exclusion criteria
The below
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety as assessed by mumber of participants with treatment-related adverse events assessed on MRI scan | 24 months | Number of participants with treatment-related adverse events assessed on MRI scan |
| Memory change tested on Ray Auditory Verbal Learning Task | 24 months | Memory tested on Ray Auditory Verbal Learning Task |
| Memory change tested on Benson Complex Figure Draw and Memory | 24 months | Memory tested on Benson Complex Figure Draw and Memory |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy on PET scan reflected by change in fluorodeoxyglucose (FDG) PET scan | 24 months | FDG PET scan |
| Change in Biomarkers including CSF amyloid, tau and neurofilament | 24 months | CSF studies of amyloid, tau and neurofilament |
| Memory change tested on mini-mental status examination (MMSE) | 24 months | MMSE |
| Memory tested on Alzheimer's Disease Assessment Scale, Cognitive component (ADAS-Cog) | 24 months | ADAS-Cog |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORMark Tuszynski, M.D., Ph.D.
University of California, San Diego
Outcome results
None listed