Inclusion criteria:
* Age \>18 years of age
* Chronic non-ischemic cardiomyopathy
* LVEF 15% ≤ 30% by transthoracic echocardiography (TTE) within 6 months prior to enrollment
* NYHA Class III HF for a minimum of 3 months HF despite appropriate medical therapy (defined below):
* Treatment with appropriate HF therapy as tolerated, including, but not limited to:
* Beta blocker therapy and angiotensin converting enzyme (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; and
* Cardiac resynchronization therapy (CRT), 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
* Females 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 administration
* Intrauterine device in place for at least 90 days prior to receiving IP
* Barrier methods (diaphragm plus spermicide or condom) starting at least 30 days prior to receiving IP
* Abstinence (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 subject
* Surgical sterilization of the partner(s) (vasectomy) for \>180 days prior to IP administration
* Hormonal 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 contraceptives
* Males subjects capable of fathering a child:
* Must agree to use a condom from IP administration through 6 months after the time of IP administration
* Must agree not to donate sperm for 6 months after time of receiving IP
* Documented evidence of vasectomy in males for 180 days minimum prior to receiving IP is an acceptable form of contraception
* Males 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 subject
* Ability to sign Informed Consent Form (ICF) and Release of Medical Information Form
* Appropriate candidate for protocol-specified intracoronary infusion in the judgment of the infusing interventional cardiologist
Cohort 3: medical history documentation of PLN-R14Del mutation and an ICD in situ (at least 30 days prior to enrollment)
Exclusion Criteria:
* Chronic ischemic cardiomyopathy
* Intravenous (IV) inotropic therapy, intra-aortic balloon pump (IABP) or percutaneous cardiac assist device therapy within 30 days prior to enrollment
* Restrictive cardiomyopathy, obstructive cardiomyopathy, pericardial disease, amyloidosis, infiltrative cardiomyopathy, uncorrected thyroid disease, or dyskinetic LV aneurysm
* Cardiac surgery or percutaneous coronary intervention (PCI) within 30 days prior to enrollment
* Third degree heart block
* Clinically 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 enrollment
* Prior heart transplantation, left ventricular reduction surgery (LVRS), cardiomyoplasty, passive restraint device (e.g., CorCap™ Cardiac Support Device), surgically implanted LVAD or cardiac shunt
* Likely to receive cardiac resynchronization therapy, cardiomyoplasty, LV reduction surgery, heart transplant, conventional revascularization procedure, or valvular repair within 3 months of IP dosing
* Known hypersensitivity to contrast dyes 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 investigator
* Active or suspected infection within 48 hours prior to enrollment as evidenced by fever or positive culture
* Known intrinsic liver disease (e.g., cirrhosis, hepatitis A, chronic hepatitis B or hepatitis C virus infection). If serology is positive and PCR is 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.
* Renal Failure, dialysis dependent or serum creatinine \> 2.5 mg/dl within 30 days prior to enrollment
* Bleeding diathesis or thrombocytopenia defined as platelets \<50,000 platelets/μL within 30 days prior to enrollment
* Anemia defined as hemoglobin \<10 g/dL or transfusion dependent within 30 days prior to enrollment
* Neutropenia defined as absolute neutrophils \<1500 mm3 within 30 days prior to enrollment
* 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
* Receiving investigational intervention or participating in another clinical study within 30 days or within 5 half-lives of another investigational drug administration prior to administration of NAN-101 that may impact the therapeutic potential of NAN-101.
* Pregnancy or breastfeeding at the time of screening