Efficacy and Safety Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

Inclusion Criteria:

Chronic ischemic or non-ischemic cardiomyopathy. Subjects with ischemic cardiomyopathy must have at least one major coronary vessel with Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow.
Left ventricular ejection fraction (LVEF) ≤35%
Diagnosis of New York Heart Association (NYHA) Class III/IV heart failure for a minimum of 3 months prior to screening
Maximal oxygen consumption (VO2 max) ≤20 mL/kg/min within 90 days prior to enrollment
An implantable cardioverter defibrillator (ICD) implanted a minimum of 30 days prior to enrollment
Treatment with appropriate heart failure therapy as tolerated
All women of childbearing potential must have a negative urine pregnancy test prior to administration of investigational product and agree to use adequate contraception. Men capable of fathering a child must agree to use barrier contraception or limit activity to post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3 months after administration of investigational product.
Ability to sign Informed Consent Form (ICF) and Release of Medical Information Form

Exclusion Criteria:

Any intravenous therapy with positive inotropes, vasodilators, or diuretics within 30 days prior to enrollment
Restrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysm
Cardiac surgery, percutaneous coronary intervention, or valvuloplasty within 30 days prior to enrollment
Clinically significant myocardial infarction (e.g., ST elevation MI [STEMI] or large non-STEMI) within 6 months prior to enrollment
Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCapâ„¢ Cardiac Support Device), surgically implanted LVAD or cardiac shunt
Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, heart transplant, conventional revascularization procedure, or valvular repair within 6 months following enrollment
Patients with prior coronary artery bypass graft(s) (CABG) will reviewed on a case-by-case basis
No evidence of functional or viable myocardium
Exercise capacity primarily limited by obesity, peripheral vascular disease, intrinsic pulmonary disease or orthopedic problems and not by underlying heart failure
Known hypersensitivity to octafluoropropane (component of the intravenous echocardiography contrast agent, DEFINITY®) or other contrast dyes used for angiography; history of, or likely need for, high dose steroid pretreatment prior to contrast angiography
A left ventricle that is difficult to image or high quality echocardiography is not obtainable at screening
Significant left main or ostial right coronary lumenal stenosis in the opinion of the investigator
Expected survival <1 year in the investigator's medical opinion
Suspected or active viral, bacterial, fungal, or parasitic infection within 48 hours prior to enrollment
Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase) >2x Upper Limit of Normal (ULN) within 30 days prior to enrollment or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection)
Current or likely need for hemodialysis within 12 months following enrollment
Bleeding diathesis or thrombocytopenia defined as platelet count <50,000 platelets/μL
Anemia defined as hemoglobin <10 g/dL
Known AIDS or HIV-positive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3
Previous participation in a study of gene transfer
Presence of neutralizing anti-AAV1 antibodies at titer ≥1:2 within 3 months of screening
Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the investigational drug administration prior to enrollment
Pregnancy or lactation
Recent history of psychiatric disease (including drug or alcohol abuse) that is likely to impair subject's ability to comply with protocol-mandated procedures, in the opinion of the investigator
Other concurrent medical condition(s) that, while not explicitly excluded by the protocol, could jeopardize the safety of the patient or objectives of the study