A Phase 2, Adaptive, Double-blinded, Placebo Controlled, Randomized, Multicenter Trial to Evaluate the Efficacy, Safety and Tolerability of Intracoronary Infusion of NAN-101 in Adult Subjects With New York Heart Association (NYHA) Class III Heart Failure and Non-ischemic Cardiomyopathy

This is a Phase 2 adaptive, double-blinded, placebo-controlled, randomized, multi-center trial study to evaluate the safety and efficacy of a single dose of NAN-101, administered via antegrade intracoronary artery infusion, in males and females age >18 years with non-ischemic cardiomyopathy and NYHA Class III symptoms of HF.Subjects will be randomized into one of three treatment groups in a 1:1:1

Inclusion Criteria:Subject must be age ≥18 years of age, at the time of signing the informed consent.Chronic non-ischemic cardiomyopathy15% ≤ LVEF ≤ 35% by transthoracic echocardiography (TTE) at screening6MWT >50 metersMedically stable, NYHA Class III HF for a minimum of 4 weeks while on appropriate medical therapy (defined below) including, but not limited to:Beta blocker therapy and ACE inhibitor or angiotensin receptor blocker (ARB) or sacubitril/valsartan combination therapy (Entresto) for ≥ 90 days prior to enrollment.May also receive aldosterone antagonist therapy. Doses of the above medications must be stable for ≥ 30 days prior to enrollment; andCardiac resynchronization therapy (Zareba et al 2011), if clinically indicated, must have been implanted ≥ 90 days prior to enrollment. Internal cardioverter defibrillator (ICD) must be implanted, if clinically indicated ≥ 30 days prior to enrollment.Women of childbearing potential must use at least one of the following acceptable birth control methods throughout the study and for 6 months after IP administration:Surgically sterile (bilateral tubal ligation, hysterectomy, bilateral oophorectomy) 6 months minimum prior to IP administrationIntrauterine device in place for at least 90 days prior to receiving IPBarrier methods (diaphragm plus spermicide or condom) starting at least 30 days prior to receiving IPAbstinence (the subject must be willing to remain abstinent from screening to 6 months after receiving IP). Females are allowed to claim abstinence as their method of contraception only when it is the preferred and usual lifestyle of the subjectSurgical sterilization of the partner(s) (vasectomy) for >180 days prior to IP administrationHormonal contraceptives starting > 90 days prior to IP. If hormonal contraceptives are started less than 90 days prior to receiving IP, subjects must agree to use a barrier method (diaphragm plus spermicide or condom) from screening through 90 days after initiation of hormonal contraceptivesMales subjects capable of fathering a child:Must agree to use a condom and should also be advised of the benefit for a female partner to use a highly effective method of contraception as a condom may break or leak when having sexual intercourse with a woman of childbearing potential who is not currently pregnant from IP administration through 6 months after the time of IP administrationMust agree not to donate sperm for 6 months after time of receiving IPDocumented evidence of vasectomy in males for 180 days minimum prior to receiving IP is an acceptable form of contraceptionMales who claim abstinence as their method of contraception are allowed, provided they agree to use barrier methods should they become sexually active from screening through 6 months after receiving IP. Males are allowed to claim abstinence as their method of contraception only when it is the preferred and usual lifestyle of the subjectAppropriate candidate for protocol-specified intracoronary infusion in the judgment of the infusing interventional cardiologistExclusion Criteria:Subjects are excluded from the study if any of the following criteria apply:Chronic ischemic cardiomyopathy secondary to obstructive coronary artery diseaseIntravenous (IV) inotropic therapy, intra-aortic balloon pump (IABP) or percutaneous cardiac assist device therapy within 30 days prior to enrollmentRestrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysmCardiac surgery or percutaneous coronary intervention (PCI) within 30 days prior to screeningThird degree heart blockClinically significant myocardial infarction (MI) in the judgment of the subject's physician (e.g., ST elevation MI [STEMI] or large non-STEMI) within 6 months prior to enrollmentPrior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shuntLikely to receive cardiac resynchronization therapy, cardiomyoplasty, LV reduction surgery, heart transplant, conventional revascularization procedure, or valvular repair within 3 months of IP dosing in judgement of investigator.Known hypersensitivity to contrast dyes (not easily controlled by antihistamines) used for angiography; history of, or likely need for, high-dose steroid pretreatment prior to contrast angiography.Expected survival < 1 year in the judgment of the investigatorActive or suspected infection within 48 hours prior to intra-coronary infusion as evidenced by fever or positive cultureKnown intrinsic liver disease (e.g., cirrhosis, hepatitis A, chronic hepatitis B or hepatitis C virus infection). If serology is positive and PCR is known to be negative, subject may be eligible (confirm with medical monitor).Liver function tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase) > 2x upper limit of normal (ULN) within 30 days prior to enrollment.Chronic Kidney Disease Stage 5, dialysis dependent or eGFR<15 within 30 days prior to enrollmentBleeding diathesis or thrombocytopenia defined as platelets <50,000 platelets/μL within 30 days prior to enrollmentAnemia defined as hemoglobin <10 g/dL or transfusion dependent within 30 days prior to enrollmentNeutropenia defined as absolute neutrophils <1500 mm3 within 30 days prior to enrollmentKnown AIDS or HIV-positive status, or a previous diagnosis of immunodeficiency with an absolute neutrophil count <1000 cells/mm3Previous participation in a study of gene transferReceiving investigational intervention or participating in another clinical study within 30 days of another investigational drug administration prior to administration of NAN- 101 that may impact the therapeutic potential of NAN-101.Pregnancy or breastfeeding or plans to become pregnant within the next 12 months at the time of screeningSubjects with any other condition which in the opinion of the investigator would preclude participation in the study (including risk for non-compliance and any intercurrent conditions that pose an undue medical hazard, or which could interfere with the interpretation of the study results)Presence of neutralizing anti-AAV2i8 antibodies at titer of >1:5 within 6 months prior to IP administrationMalignant neoplasm within 5 years of dosing, with the exception of those with negligible risk of metastasis or death (such as adequately treated carcinoma in situs of the cervix, basal or squamous cell skin cancer, localized prostate cancer or ductal carcinoma in situ)Any documented history of non-compliance with medications, illicit drug use or laboratory evidence of illicit drug use during screen period