A Study of Genetically Targeted Enzyme Replacement Therapy for Advanced Heart Failure

Inclusion Criteria:

Unless otherwise specified, screening must be performed within 30 days prior to
administration of investigational medicinal product on Day 0 except as noted under
Inclusion Criteria #1 and 4. Subjects must meet the following criteria to be eligible for
the study:

1. Negative neutralizing AAV1 antibodies (NAb) (titer <1:2 or equivocal) within 90 days
of screening.

2. 18-80 years of age, inclusive, at the time of signing the informed consent.

3. Chronic systolic HF due to 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. If a subject has not
undergone coronary angiography within 2 months, this criterion may be assessed after
the subject is randomized and undergoes angiography just prior to the planned
infusion of investigational medicinal product.

1. Hypertrophic cardiomyopathy is excluded.

2. Toxic and alcoholic cardiomyopathies are allowed as long as toxin or alcohol
exposure has been eliminated and a sufficient amount of limit has elapsed to
rule-out spontaneous recovery.

4. Left ventricular ejection fraction (LVEF) ≤35% anytime during the 60-day window prior
to administration of investigational medicinal product.

5. Diagnosis of New York Heart Association (NYHA) class II, III or IV HF for a minimum
of 90 days prior to screening.

6. Individualized, maximal, optimized HF therapy consistent with American College of
Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology
(ESC) practice guidelines for the treatment of chronic heart failure (ACC/AHA/ESC 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 angiotensin-receptor
blocker (ARB) if ACE intolerant) and, as tolerated, beta blocker at approved
dosages as labeled in the respective package insert. The choice of beta blocker
is limited to those approved for heart failure in all participating countries
(bisoprolol, carvedilol or sustained release metoprolol succinate). 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; 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. Enrollment of any subject with
any deviation from this combination must be preapproved by the medical monitor.

2. Resynchronization therapy, if clinically indicated according to ACC/AHA/ESC HF
guidelines, must have been implanted at least 6 months prior to screening.

3. Implantable cardioverter defibrillator (ICD), if clinically indicated according
to ACC/AHA/ESC HF guidelines, must have been implanted a minimum of 30 days
prior to screening.

4. Cardiac rehabilitation should be consistent with the Agency for Health Care
Policy and Research Clinical Practice Guideline, Number 17, Cardiac
Rehabilitation. This does not imply that the potential candidate must be
enrolled in a cardiac rehabilitation program at screening or in the future.

7. All women of childbearing potential must have a negative urine pregnancy test prior
to administration of investigational medicinal product and agree to use adequate
contraception (defined as oral or injectable contraceptives, intrauterine devices,
surgical sterilization or a combination of a condom and spermicide) or limit sexual
activity to vasectomized partner for 3 months after administration of investigational
medicinal product. Men capable of fathering a child must agree to use barrier
contraception (combination of a condom and spermicide) or limit activity to
post-menopausal, surgically sterilized, or a contraception-practicing partner, for 3
months after administration of investigational medicinal product.

8. Ability to understand and comply with study requirements as evidenced by providing
signed written informed consent form and Release of Medical Information Form.

9. Presence of at least one of the following risk factors:

1. Hospitalization for heart failure 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 heart failure (e.g., intravenous diuretics,
peripheral ultrafiltration)

2. N-terminal pro-B-type natriuretic peptide (NT-proBNP) >1200 pg/mL (BNP >225
pg/mL) within 30 days of screening; if subject is in atrial fibrillation,
NT-proBNP >1600 pg/mL (BNP >275 pg/mL) within 30 days of screening

10. In Germany only: Medically indicated for diagnostic angiography at the clinician's
discretion.

Exclusion Criteria:

Subjects meeting any of the following criteria will be excluded from the study:

1. Any intravenous (IV) therapy with positive inotropes, vasodilators or diuretics
within 30 days prior to screening.

2. Restrictive cardiomyopathy, obstructive cardiomyopathy, acute myocarditis,
pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid
disease or discrete LV aneurysm.

3. Cardiac surgery, percutaneous coronary intervention (PCI) or valvuloplasty within 30
days prior to screening.

4. Myocardial infarction (MI) (e.g., ST elevation MI [STEMI] or large non-STEMI) within
90 days prior to screening. Large non-STEMI shall be defined >3x upper limit of
normal (ULN) for creatinine kinase (CK)-MB or >5x ULN for troponin.

5. Prior heart transplantation, left ventricular reduction surgery (LVRS),
cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device),
surgically implanted left ventricular assist device (LVAD) or cardiac shunt.

6. Likely need for an immediate heart transplant or LVAD implant due to hemodynamic
instability.

7. Prior coronary artery bypass grafting (CABG) is not considered ideal for inclusion in
the study; however, a potential candidate can be reviewed on a case-by-case basis.
Ideally, the orifice of the graft should be easy to engage with a catheter and the
graft should perfuse a significant amount of potentially viable myocardium.

8. Known hypersensitivity to contrast agents used for angiography; history of, or likely
need for, high dose steroid pretreatment prior to contrast angiography.

9. Significant, in the opinion of the investigator, left main or ostial right coronary
luminal stenosis.

10. Liver function tests (alanine amino transferase [ALT], aspartate aminotransferase
[AST], alkaline phosphatase) >3x ULN within 30 days prior to investigational
medicinal product administration or known intrinsic liver disease (e.g., cirrhosis,
chronic hepatitis B or hepatitis C virus infection).

11. 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) calculation.

12. Bleeding diathesis or thrombocytopenia defined as platelet count <50,000
platelets/μL.

13. Anemia defined as hemoglobin <9 g/dL, provided that there is no evidence of bleeding.

14. Known AIDS or HIV seropositive status, or a previous diagnosis of immunodeficiency
with an absolute neutrophil count <1000 cells/mm^3.

15. Diagnosis of, or treatment for, any cancer other than basal cell carcinoma within the
last 5 years. (Past medical history of cancer is not exclusionary as long as subject
has been disease-free for at least 5 years since the time of diagnosis and
treatment).

16. 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.

17. Receiving investigational intervention or participating in another clinical study
within 30 days or within 5 half-lives of the investigational drug administration
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.

18. Pregnant or breast-feeding.

19. Recent history of psychiatric disease, including drug or alcohol abuse, that is
likely to impair, in the opinion of the investigator, the subject's ability to comply
with protocol-mandated procedures.

20. Other concurrent medical condition(s) that, while not explicitly excluded by the
protocol, could jeopardize the safety of the subject or objectives of the study.