CALM-AF-AI: Counteracting Age-related Loss of Muscle With AAV-Follistatin Combined With Angiogenesis-Inducing VEGF Plasmid Gene Therapy

Exclusion Criteria74

• Pregnancy, breastfeeding, or intent to become pregnant; premenopausal status (unless ≥12 months amenorrhea or FSH ≥30 IU/L)
• Subjects who have a history of alcohol or drug abuse within 1 year of study entry
• Initiation of prohibited medications, supplements, or interventions during the study period that may confound efficacy or safety assessments
• Active malignancy
• History of malignancy
• Strong family history of cancer in first-degree relatives (≥2 relatives with cancer diagnosed <60 years)
• Known hereditary cancer syndrome (BRCA1/2, Lynch syndrome, Li-Fraumeni, FAP, HNPCC) without genetic counseling and enhanced surveillance clearance
• History of stroke or transient ischemic attack (TIA)
• History of myocardial infarction (MI) or unstable angina (regardless of time since event)
• Diagnosed coronary artery disease (CAD) documented by coronary angiography or stress testing
• Significant atherosclerotic disease at any location (stenosis ≥50% in carotid, femoral, or other major arteries)
• Prior coronary revascularization (percutaneous coronary intervention \[PCI\] or coronary artery bypass grafting \[CABG\])
• Prior valvular repair or replacement
• History or current diagnosis of heart failure
• Uncontrolled hypertension (SBP >140 mmHg or DBP >85 mmHg despite treatment)
• Left ventricular ejection fraction (LVEF) <50%, QTc ≥480 ms, or severe valvular heart disease
• Ventricular arrhythmias requiring chronic drug treatment or implantable cardioverter-defibrillator
• Presence of pacemaker or persistent left bundle branch block
• Known diagnosed cardiomyopathy of any etiology
• Significant left ventricular hypertrophy, defined as maximal left ventricular wall thickness ≥15 mm in any segment at end-diastole (by echocardiography or cardiac MRI)
• History of venous thromboembolism (DVT, PE, or thrombosis at any site), particularly if unprovoked, or associated with only minor provoking factors (e.g., minor surgery, combined oral contraceptives, short-term immobilization)
• Recurrent thrombotic events, including recurrent superficial venous thrombosis
• Thrombosis at unusual sites (e.g., mesenteric, portal, or splenic vein thrombosis, Cerebral venous sinus thrombosis, Hepatic vein thrombosis (Budd-Chiari syndrome), Renal vein thrombosis, Retinal vein thrombosis)
• Superior vena cava thrombosis not related to central venous catheterization
• Strong family history of venous or arterial thrombosis at a young age in first-degree relatives
• History of recurrent pregnancy loss or severe obstetric complications suggestive of a hypercoagulable state
• High-degree myopia (≥ -6.0 diopters) or pathological myopia without ophthalmologic clearance
• History of retinal detachment, vitreous hemorrhage, or retinal vascular disease (diabetic retinopathy, retinal vein occlusion, age-related macular degeneration with neovascularization)
• Use of systemic anti-VEGF therapy (e.g., bevacizumab)
• Current use of prohibited medications or supplements (see Section 4.3)
• Fasting plasma glucose ≥6.0 mmol/L (≥108 mg/dL) at screening
• HbA1c ≥6.5% (≥48 mmol/mol) at screening
• Known history of diabetes mellitus (any type)
• History of peptic ulcer disease within 12 months
• Known osteoporosis (DXA T-score ≤ -2.5 at the hip or spine)
• Severe pulmonary disease, including COPD or restrictive lung disease (FVC <49% predicted)
• Advanced renal disease (CKD stage 3-5, eGFR <60 mL/min/1.73 m²) or dialysis dependence
• History of cirrhosis or cholestatic liver disease
• Chronic viral hepatitis (HBV, HCV)
• Autoimmune hepatitis
• Active hepatitis or evidence of hepatic decompensation
• ALT or AST >1.5× upper limit of normal (ULN)
• Total bilirubin >1.5× ULN (unless due to Gilbert's syndrome)
• Active cholecystitis, symptomatic gallbladder disease (e.g., biliary colic), or any other clinically significant hepatobiliary abnormality
• Neurodegenerative disease
• Neuromuscular disorder
• Psychiatric or movement disorders impairing participation
• History of drug-induced myopathy or rhabdomyolysis
• Elevated creatine kinase (CK) at screening CK >1.0× ULN confirmed on two separate occasions at least 48 hours apart
• Systemic lupus erythematosus (SLE), including overlap or drug-induced forms
• Mixed connective tissue disease (MCTD)
• Systemic sclerosis (diffuse, limited, or sine scleroderma)
• Inflammatory myopathies (including polymyositis, dermatomyositis, inclusion body myositis, immune-mediated necrotizing myopathy, or overlap myositis)
• Primary Sjögren's syndrome requiring systemic immunosuppression
• Rheumatoid arthritis requiring biologic therapy or with extra-articular manifestations
• Undifferentiated connective tissue disease meeting ≥2 classification criteria
• Current or recent use of immunosuppressive agents (within 3 months)
• Acute bacterial, fungal, or viral infection, fever, or receipt of live vaccines within 30 days prior to screening
• Active hepatitis B infection or reactivation risk (HBsAg positive, HBV DNA detectable, or isolated anti-HBc without anti-HBs)
• Hepatitis C infection (detectable HCV RNA or treatment within 6 months)
• HIV infection
• Active or latent tuberculosis (positive QuantiFERON-TB Gold Plus ≥0.35 IU/mL)
• Acute herpesvirus infection, defined as Active HSV-1 or HSV-2 lesions (vesicles, ulcers, crusts) on clinical examination at screening, CMV or EBV IgM positive
• Platelet count <100 × 10⁹/L at screening
• Active therapeutic anticoagulation
• Known inherited or acquired coagulation disorder
• Use of anticoagulants that cannot be safely discontinued prior to study treatment
• Severe physical functional limitation (6-Minute Walk Test distance <150 meters or CFS>6)
• Prior exposure to any AAV gene therapy product (any AAV serotype)
• Prior exposure to any investigational drug within 90 days
• Participation in another clinical trial within 90 days
• Known hypersensitivity to investigational product components or immunosuppressive agents (e.g., prednisone, rapamycin)
• Life expectancy <6 months
• Any condition that, in the Investigator's judgment, may pose undue risk, interfere with study outcomes, or impair study participation