AC6 Gene Transfer for CHF

This research study is designed to determine: 1) whether gene transfer using an agent called
Ad5.hAC6 (adenovirus-5 encoding human adenylyl cyclase type 6) can be given safely to
patients with congestive heart failure (CHF) and 2) whether this agent may be of benefit in
heart failure. Gene transfer is a process by which genes are introduced into cells and the
cells then produce the specific protein that the gene directs, in this case, a protein known
as adenylyl cyclase type 6 (AC6). The gene is carried into the heart cells by a modified
virus. The virus that is modified is an adenovirus (Ad5), a virus that sometimes causes a
brief cold. In extensive animal experiments, it was found that increased amounts of AC6
protein in heart cells appear to make the heart pump more vigorously.

Inclusion Criteria

1. Male or non-pregnant female patients aged 18-80 years of age

2. ≥3-month history of heart failure

3. Compensated (stable) CHF not on intravenous inotropes, vasodilators or diuretics, on
optimal medical and device therapy as defined by AHA/ACC Guidelines

4. LV ejection fraction (on optimal therapy) no greater than 40%

5. Implanted cardiac defibrillator

6. At least one major coronary artery (or graft) with <50% proximal obstruction

7. Patients unable to walk (spinal injury, orthopedic problems) can be enrolled if all
other criteria are met.

8. Women of child-bearing capacity must have a negative pregnancy test within 2 days of
test substance administration, and female and male patients must be willing to use
birth control during sex for 12w after test substance administration if the female
partner is of child-bearing capacity.

9. Subjects willingly provide informed consent consistent with ICH-GCP guidelines

Exclusion Criteria

1. Unstable or Class IV angina

2. Coronary revascularization planned or predicted in next 6 months

3. Ischemic myocardium in 3 or more regions of a single perfusion bed, as assessed by
stress echocardiography or jeopardized viable myocardium >15% on perfusion imaging.

4. ≥50% occlusion of an "unprotected" left main coronary artery. If arterial or venous
conduits provide blood flow to the distal left coronary circulation (ie, patent bypass
grafts) then left main disease is "protected" and such patients are not excluded. The
cardiologist performing the cardiac catheterization will make these decisions.

5. 2° AV Block (Mobitz 2) or 3° AV block unless pacemaker is present

6. Hospitalization for CHF requiring intravenous inotropes or vasodilators in the past 4
weeks

7. History of biopsy proven myocarditis

8. Myocardial infarction in previous 6 months

9. Restrictive, hypertrophic or infiltrative cardiomyopathy or chronic pericarditis

10. Previous or planned organ transplant recipient or donor.

11. Thrombocytopenia (<100,000 platelets/µl) or bleeding diathesis

12. COPD requiring supplemental oxygen at home

13. AST > 2 times upper limit of normal or chronic liver disease such as cirrhosis or
Hepatitis C Virus (HCV). Patients with HCV are eligible only if both of two conditions
are met: a) liver function tests are normal; AND b) liver biopsy is normal or shows
only mild fibrosis.

14. Current or predicted hemodialysis within 12 months or estimated glomerular filtration
rate (EGFR) <30 ml/min. On online EGFR calculator that uses sex, age, body weight and
serum creatinine is available at:
www.kidney.org/professionals/kdoqi/gfr_calculator.cfm. Use the higher of two EGFR
results, which are based upon MDRD and CKD-EPI formulas.

15. CVA or TIA <6 months prior to enrollment

16. Patients who are immunosuppressed by medicines (corticosteroids, methotrexate,
cyclophosphamide, cyclosporine), illnesses (AIDS, HIV), or neutrophil count <1000/mm3

17. Patients receiving other investigational drug therapy within 30 days of enrollment
including gene transfer

18. Patients with diseases other than CHF that, in the opinion of the investigator, put
the subject at risk or adversely affect the results