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

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 probableAD 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. Inparticular:

7. Subjects taking stable doses of antidepressants lacking significantanti-cholinergic side effects are acceptable (if they are not currentlydepressed and do not have a history of major depression within the past twoyears).

8. Estrogen-replacement therapy is permissible.

9. Anti-cholinesterases and memantine are allowed (stable doses for preceding 3months).

10. Geriatric Depression Rating scale indicates no depression (Geriatric DepressionScale not greater than 8 on GDS-30).

11. A caregiver is available who has frequent contact with the subject (e.g., an averageof ten hours/week or more), agrees to observe for adverse events, and will accompanythe subject to all clinic visits for the duration of the protocol.

12. CT or MRI scans within 24 months prior to screening without evidence of aninfection, infarction, or other focal (e.g., subdural hematomas) or generalizedlesions (e.g., hydrocephalus) and without clinical symptoms suggestive ofintervening neurological disease. A lacune in a non-critical brain area that is notbelieved to contribute to the cognitive impairment is permissible.

13. Adequate visual and auditory acuity to allow neuropsychological testing thatrequires visual and auditory acuity.

14. Good general health with no additional diseases expected to interfere with the studyin the opinion of the investigator.

15. Normal serum B12, RPR, and thyroid function tests; or clinically insignificantabnormalities that would not be expected to interfere with the study.

16. ECG without clinically significant abnormalities that would be expected to interferewith the study.

17. Subject is not pregnant, lactating, or of child-bearing potential (i.e., women mustbe 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-AAcriteria 16. The diagnosis of MCI is also internationally recognized as the currentstandard for diagnosing MCI.

2. Mini-Mental State Exam score between 24 and 29 (inclusive) and examinationconsistent with diagnosis of MCI. We will not require CSF biomarkers forsubclassifying 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. Inparticular:

7. Subjects taking stable doses of antidepressants lacking significantanti-cholinergic side effects are acceptable (if they are not currentlydepressed and do not have a history of major depression within the past twoyears).

8. Estrogen-replacement therapy is permissible.

9. Anti-cholinesterases and memantine are allowed (stable doses for preceding 3months).

10. Geriatric Depression Rating scale indicates no depression (Geriatric DepressionScale not greater than 8 on GDS-30).

11. A caregiver is available who has frequent contact with the subject (e.g., an averageof ten hours/week or more), agrees to observe for adverse events, and will accompanythe subject to all clinic visits for the duration of the protocol.

12. CT or MRI scans within 24 months prior to screening without evidence of aninfection, infarction, or other focal (e.g., subdural hematomas) or generalizedlesions (e.g., hydrocephalus) and without clinical symptoms suggestive ofintervening neurological disease. A lacune in a non-critical brain area that is notbelieved to contribute to the cognitive impairment is permissible.

13. Adequate visual and auditory acuity to allow neuropsychological testing that was avisual and auditory acuity.

14. Good general health with no additional diseases expected to interfere with the studyin the opinion of the investigator.

15. Normal serum B12, RPR, and thyroid function tests; or clinically insignificantabnormalities that would not be expected to interfere with the study.

16. ECG without clinically significant abnormalities that would be expected to interferewith the study.

17. Subject is not pregnant, lactating, or of child-bearing potential (i.e., women mustbe post-menopausal or surgically sterile).

Exclusion Criteria:

The below Exclusion Criteria apply to both the AD and MCI groups.

1. 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, subduralhematoma, multiple sclerosis, arteriovenous malformation or history of significanthead trauma followed by persistent neurologic deficits or known structuralabnormalities.

2. Individual has symptoms of aphasia which would make administration of studyassessments and collection of information during study challenging.

3. Major depression or another major psychiatric disorder as described in DMS-IV withinthe past two years.

4. Psychotic features, agitation or behavioral problems within the last three monthswhich could lead to difficulty in cooperating with study.

5. History of alcohol or substance abuse or dependence within the past two years (DMS-IV criteria).

6. History of schizophrenia (DMS-IV criteria).

7. Affirms suicidal ideation in response to questions number 4 or 5 in the C-SSRSduring 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 theC-SSRS as applicable during the past 12 months.

8. History of systemic cancer within the past 18 months (non-metastatic skin cancersare acceptable).

9. Any significant systemic illness or unstable medical conditions which could lead todifficulty complying with the protocol including:

10. History of myocardial infarction in the past year or unstable or severecardiovascular disease including angina or congestive heart failure withsymptoms at rest.

11. Clinically significant obstructive pulmonary disease or asthma.

12. Clinically significant and unstable gastrointestinal disorder; i.e., ulcerdisease or history of active or occult gastrointestinal bleeding within twoyears.

13. Clinically significant test abnormalities on the battery of screening tests (hematology, prothrombin time, chemistry, urinalysis, ECG).

14. Insulin-requiring diabetes or uncontrolled diabetes mellitus.

15. Uncontrolled hypertension (systolic blood pressure greater than 180 ordiastolic blood pressure greater than 110).

16. History of clinically significant liver disease, coagulopathy, or Vitamin Kdeficiency within the past two years.

17. History of uncorrected hypothyroidism.

18. Excluded Medications

19. Use of centrally active beta-blockers, narcotics, methyldopa, or clonidinewithin four weeks prior to screening.

20. Use of anti-Parkinsonian medications (e.g., Sinemet®, amantadine,bromocriptine, pergolide and selegiline) within two months prior to screening.

21. Use of neuroleptics or narcotic analgesics within four weeks prior toscreening.

22. Use of long-acting benzodiazepines or barbiturates within four weeks prior toscreening.

23. Use of short-acting anxiolytic or sedative hypnotics more frequently than twotimes per week within four weeks prior to screening (note: sedative agentsshould not be used within 72 hours of screening).

24. Initiation or change in dose of an antidepressant lacking significantcholinergic side effects within the four weeks prior to screening (use ofstable doses of antidepressants for at least 4 weeks prior to screening isacceptable).

25. Use of systemic corticosteroids within three months prior to screening.

26. Use of medication with significant cholinergic or anticholinergic side effects (e.g., pyridostigmine, tricyclic antidepressants, meclizine, and oxybutynin)within four weeks prior to screening.

27. Use of anticonvulsants (phenytoin, phenobarbital, carbamazepine, valproate)within two months prior to screening.

28. Use of anticoagulant therapy within four weeks prior to screening.

29. Use of Anti-amyloid monoclonal antibodies not permissible within 1 month ofTreatment (Day 0) Vector Delivery.

30. Use of any investigational drugs within thirty days or five half-lives, whichever islonger, prior to Treatment (Day 0) Vector Delivery.

31. Any contraindication for undergoing MRI (e.g., pacemakers, epicardial pacer wires,infusion pumps, surgical and/or aneurysm clips, shrapnel, metal prosthesis, implantswith potential magnetic properties, metallic bodies in the eyes, etc.) orcontraindication to receiving gadolinium and other imaging contrast agents.

32. Subjects who, in the investigators' opinion, will not comply with study procedures.

33. Any history of gene therapy to include RNA or DNA targeted Alzheimer's Diseasespecific investigational agents.