A Phase 1/2 Study of High-dose Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

Inclusion Criteria: * Unless otherwise specified, screening must be performed within 30 days prior to enrollment (phase 1) or enrollment/randomization (phase 2) except as noted below. Subjects must meet the following criteria to be eligible for the study: 1. AAV1 neutralizing antibodies (NAb) negative (titer \<1:2 or equivocal) within 60 days prior to screening. 2. Age 18-80 years, inclusive, at the time of signing the first informed consent. 3. Chronic ischemic or non-ischemic cardiomyopathy, except for hypertrophic cardiomyopathy. Toxic or alcoholic cardiomyopathies are allowed as long as toxin or alcohol exposure has been eliminated and a sufficient amount of time has elapsed to rule out spontaneous recovery. Similarly, patients with viral or peripartum cardiomyopathy will not be enrolled until sufficient time has elapsed to rule out spontaneous recovery. Subjects with ischemic cardiomyopathy must have at least 1 major coronary vessel with thrombolysis in myocardial infarction (TIMI) grade 3 flow. (If a subject has not undergone recent coronary angiography, TIMI flow may be assessed during the study angiography just prior to investigational medicinal product \[IMP\] infusion). 4. Left ventricular ejection fraction ≤35%. 5. Diagnosis of New York Heart Association class III/IV heart failure (HF) for a minimum of 60 days prior to screening. 6. For phase 2 only, the presence of at least one of the following risk factors: 1. Hospitalization for HF within 6 months of screening, or in lieu of hospitalization, at least 2 outpatient interventions for the intended treatment of signs and symptoms of worsening HF (e.g., intravenous \[IV\] diuretics, peripheral ultrafiltration). 2. N-terminal prohormone brain natriuretic peptide (NT-proBNP) \>1200 pg/mL within 30 days of screening; if subject is in atrial fibrillation, NT-proBNP \>1600 pg/mL within 30 days of screening. 7. Individualized, maximal, optimized HF therapy consistent with American College of Cardiology/American Heart Association practice guidelines for the treatment of chronic heart failure (ACC/AHA HF guidelines) and as updated from time to time: 1. Medical therapy, as appropriate to the individual subject, including oral diuretic, angiotensin-converting enzyme (ACE) inhibitor or, if ACE intolerant, angiotensin-receptor blocker and beta blocker at approved dosages as labeled in the respective package insert and optimized for the subject. * The choice of beta blocker is limited to those approved for HF (bisoprolol, carvedilol or metoprolol succinate). Metoprolol tartrate is not approved for HF and is not allowed. * Unless contraindicated or not tolerated, the addition of an aldosterone antagonist should be considered in the absence of hyperkalemia and significant renal dysfunction and according to evolving standards. However, the final decision is at the discretion of the investigator. * Dosing of the above medications must be stable for a minimum of 30 days prior to screening, although up- or down-titration of diuretics, as medically indicated, is permitted. * Patients requiring IV diuretics during this period will be required to undergo an additional 30 day period of stabilization on oral diuretics. * Enrollment of any subject with any deviation from these criteria must be preapproved by the medical monitor. 2. Resynchronization therapy, if clinically indicated according to ACC/AHA HF guidelines, must have been initiated at least 6 months prior to screening. 3. If the subject is already participating in a cardiac rehabilitation program, it should be consistent with the current clinical practice and guidelines and continue at least through the 12-Month Active Observation Period. This does not imply that the potential candidate must be enrolled in a cardiac rehabilitation program at screening or in the future. 8. Implantable cardioverter defibrillator is required and must have been implanted a minimum of 30 days prior to screening. 9. All male subjects regardless of fertility status or the fertility status of their partner must agree to use a condom and spermicide during any sexual relations for 6 months following IMP administration to protect their partner from potential viral shedding. 10. All subjects regardless of fertility status or the fertility status of their partner must agree to have any male partner use a condom and spermicide during any sexual relations for 6 months following IMP administration to protect their partner from potential viral shedding. 11. All subjects capable of procreation with their partners must agree to use adequate contraception for 6 months following IMP administration to avoid pregnancy (defined as oral or injectable contraceptives, intrauterine devices, surgical sterilization in addition to/or a combination of a condom and spermicide). 12. Agree to not donate sperm or oocytes for 6 months following IMP administration. 13. Ability to sign Informed Consent Form and Release of Medical Information Form. Exclusion Criteria: * Subjects meeting any of the following criteria will be excluded from the study: 1. De novo diagnosis of heart failure. 2. Any IV therapy with positive inotropes, vasodilators or diuretics within 30 days prior to screening or enrollment. 3. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease or discrete left ventricular aneurysm. 4. Cardiac surgery, percutaneous coronary intervention, valvuloplasty or valve replacement within 30 days prior to screening. 5. Myocardial infarction (e.g., ST elevation myocardial infarction \[STEMI\] or large non-STEMI) within 90 days prior to screening. Large non-STEMI shall be defined \>3x the upper limit of normal (ULN) for creatinine kinase test or \>5x ULN for troponin. 6. Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), mechanical circulatory support device (MCSD) or cardiac shunt. 7. Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LVRS, conventional revascularization procedure or valvular repair in the 6 months following treatment. 8. Likely need for an immediate heart transplant or MCSD implant due to hemodynamic instability. 9. Prior coronary artery bypass graft(s) is not necessarily exclusionary. A potential candidate should be reviewed on a case-by-case basis by the treating interventionist, taking into account the dominance of the system, the accessibility of the graft(s) orifice, and the contribution of the graft vessel(s) and native coronary arteries to viable myocardial perfusion. The case and tentative infusion strategy must be discussed with the medical or safety officer prior to enrollment of the subject into the study. 10. Known hypersensitivity to radiopaque agents used for angiography; history of or likely need for, high dose corticosteroid pretreatment prior to contrast angiography. 11. Significant, in the opinion of the investigator, left main or ostial right coronary luminal stenosis. 12. Liver function tests (alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase) \>3x ULN, total bilirubin \>2x ULN or known intrinsic liver disease (e.g., cirrhosis, chronic hepatitis B or hepatitis C virus infection). 13. Current or likely need for hemodialysis within 12 months following enrollment or current glomerular filtration rate (GFR) ≤20 mL/minute/1.73 m\^2 estimated by Modification of Diet in Renal Disease (MDRD) formula for calculating the GFR MDRD calculation. 14. Bleeding diathesis or thrombocytopenia defined as platelet count \<75,000 platelets/μL. 15. Anemia defined as hemoglobin \<9 g/dL. 16. Diagnosis of, or treatment for, any cancer within the last 5 years except for basal cell carcinoma or carcinomas in situ where surgical excision was considered curative. (Past medical history of cancer is not exclusionary as long as the subject has been disease free for at least 5 years since the time of diagnosis and treatment). 17. Previous participation in a study of gene transfer; however, if the study was unblinded or documentation otherwise exists that the subject was randomized to the placebo control group and did not receive active gene transfer agent, the subject may be considered for this study. 18. Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of the drug prior to screening. Exception may be made if the individual is enrolled in a non-therapeutic observational study (registry) or the observational portion of a therapeutic study where the sponsoring authority authorizes enrollment. 19. Pregnancy or lactation. 20. 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. 21. 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.