CALM-AF-AI: Counteracting Age-related Loss of Muscle With AAV-Follistatin Combined With Angiogenesis-Inducing VEGF Plasmid Gene Therapy
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 12
- 试验地点
- 1
- 主要终点
- Number of participants with treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs)
研究概览
简要总结
This Phase 1/2a, open-label, non-randomized study is designed to evaluate the safety and tolerability of intramuscular AAV9-Follistatin gene therapy administered either as monotherapy or in combination with a VEGF-encoding plasmid. Secondary objectives include the assessment of preliminary signals of biological and functional activity, including changes in skeletal muscle mass and performance.
详细描述
Approximately 12 participants (with a potential expansion to 18-21) will be sequentially assigned to three cohorts: low-dose AAV-Follistatin monotherapy (n=3), high-dose AAV-Follistatin monotherapy (n=3), or combination therapy (AAV-Follistatin + VEGF plasmid, n=6). A cautious 3+3 dose-escalation design with sentinel dosing will be employed.
All investigational products are administered via intramuscular injection into large skeletal muscles. In Cohorts 1 and 2, AAV-Follistatin is administered once on Day 1. In Cohort 3, VEGF plasmid is administered on Day 1 and Day 12 (±2 days), followed by AAV-Follistatin on approximately Day 27 (±3 days), corresponding to 15 ± 1 days after the second VEGF plasmid dose.
Rapamycin will be administered for approximately two months to mitigate immune responses to the AAV vector. Participants will undergo regular safety monitoring, including clinical assessments, laboratory testing, and strength evaluations.
The study enrolls adults aged 35-75 years with evidence of age-related muscle decline, who are in generally stable health and able to provide informed consent and comply with study procedures. Eligible participants must demonstrate low or acceptable antibody titers to the AAV vector and hold Próspera ZEDE eResidency or Physical Residency.
Key exclusion criteria include: uncontrolled significant medical conditions; active or recent malignancy; clinically relevant immune disorders or current immunosuppressive therapy; pregnancy or breastfeeding; prior exposure to AAV-based gene therapy; or recent participation in other investigational studies.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Prevention
- 盲法
- None
入排标准
- 年龄范围
- 35 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Voluntary written informed consent obtained prior to any study-related procedures
- •Ability to read, understand, and sign the Informed Consent Form and reliably complete required study documents
- •Willingness to undergo medical intervention, including genetic therapy, and to comply with the visit schedule and all study procedures
- •Commitment to maintain a stable medication and supplement regimen throughout the study, with no initiation of new medications, supplements, or performance-enhancing substances unless approved by the Investigator
- •Men and women aged 35-75 years
- •Body mass index (BMI) between 18.0 and 35.0 kg/m² at screening
- •Active Prospera ZEDE eResidency or Physical Residency
- •Stable comorbid conditions for at least 3 months prior to screening
- •Postmenopausal status (women)
- •Willingness to use reliable contraception for 6 months following therapy
- •Low or undetectable antibody titers to AAV9 (≤1:100 by ELISA)
排除标准
- •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 or ANY history of cancer
- •Strong family history of cancer in first-degree relatives (≥2 relatives with cancer diagnosed <60 years) OR known hereditary cancer syndrome (BRCA1/2, Lynch syndrome, Li-Fraumeni, FAP, HNPCC) without genetic counseling and enhanced surveillance clearance
- •Clinically significant cardiovascular disease, including:
- •Any history of stroke, transient ischemic attack (TIA), 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 (LBBB)
- •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)
- •Known or suspected hypercoagulable state/thrombophilia, including any of the following:
- •Any 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, including but not limited to:
- •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
- •Any 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 ≥7.0 mmol/L (≥126 mg/dL) at screening
- •HbA1c ≥6.5% (≥48 mmol/mol) at screening
- •Current 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
- •Chronic liver disease or hepatic impairment:
- •Any history of cirrhosis, chronic viral hepatitis (HBV, HCV), autoimmune hepatitis, or cholestatic liver disease
- •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)
- •Non-alcoholic steatohepatitis (NASH) and clinically significant liver fibrosis
- •Active cholecystitis, symptomatic gallbladder disease (e.g., biliary colic), or any other clinically significant hepatobiliary abnormality
- 另有 30 项未显示
研究组 & 干预措施
Combination: AAV-Follistatin + VEGF Plasmid
Following safety review of Arm 2, participants in Arm 3 will receive VEGF plasmid (total dose 4.8 mg) administered intramuscularly on Day 1 and Day 12 (±2 days) across the same predefined bilateral muscle groups used for AAV-Follistatin (quadriceps femoris, gluteus maximus, gastrocnemius, and biceps brachii). AAV-Follistatin will then be administered 15 ± 1 days after the second VEGF dose (approximately Day 27-29) using the identical standardized injection map. The AAV dose for Arm 3 will be selected based on safety review of prior cohorts and will be either 5 × 10¹⁰ vg/kg or 1 × 10¹¹ vg/kg. Rapamycin will be provided per protocol for approximately two months beginning around the time of AAV administration to mitigate potential immune responses. This cohort evaluates the safety and feasibility of sequential VEGF-mediated vascular support combined with myoanabolic AAV-Follistatin gene therapy.
干预措施: VEGF Plasmid (Genetic)
Low-Dose AAV-Follistatin Monotherapy
Participants will receive a single intramuscular dose of AAV-Follistatin (5 × 10¹⁰ vg/kg) on Day 1. The total dose will be administered bilaterally across predefined injection sites in major limb muscles (quadriceps femoris, gluteus maximus, gastrocnemius, and biceps brachii) according to a standardized injection map. Rapamycin will be given per protocol for approximately two months to mitigate immune responses to the AAV vector. This sentinel cohort follows a sequential 3+3 dose-escalation design; dose-limiting toxicities will be assessed through Day 21 prior to escalation to Arm 2.
干预措施: AAV9-Follistatin gene therapy (Genetic)
High-Dose AAV-Follistatin Monotherapy
After safety review of Arm 1, participants in Arm 2 will receive a single higher intramuscular dose of AAV-Follistatin (1 × 10¹¹ vg/kg) on Day 1, administered bilaterally across predefined injection sites in major limb muscles according to the same standardized injection map. Prophylactic immunomodulation with rapamycin will be provided per protocol for approximately two months, with identical safety monitoring procedures as in Arm 1. This cohort is intended to evaluate dose-dependent safety and tolerability of AAV-Follistatin monotherapy. Dose-limiting toxicities (DLTs) will be assessed through Day 21, and escalation to Arm 3 will proceed following review of safety data and confirmation of predefined criteria.
干预措施: AAV9-Follistatin gene therapy (Genetic)
Combination: AAV-Follistatin + VEGF Plasmid
Following safety review of Arm 2, participants in Arm 3 will receive VEGF plasmid (total dose 4.8 mg) administered intramuscularly on Day 1 and Day 12 (±2 days) across the same predefined bilateral muscle groups used for AAV-Follistatin (quadriceps femoris, gluteus maximus, gastrocnemius, and biceps brachii). AAV-Follistatin will then be administered 15 ± 1 days after the second VEGF dose (approximately Day 27-29) using the identical standardized injection map. The AAV dose for Arm 3 will be selected based on safety review of prior cohorts and will be either 5 × 10¹⁰ vg/kg or 1 × 10¹¹ vg/kg. Rapamycin will be provided per protocol for approximately two months beginning around the time of AAV administration to mitigate potential immune responses. This cohort evaluates the safety and feasibility of sequential VEGF-mediated vascular support combined with myoanabolic AAV-Follistatin gene therapy.
干预措施: AAV9-Follistatin gene therapy (Genetic)
结局指标
主要结局
Number of participants with treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs)
时间窗: Day 1 through Day 90 after AAV administration
Incidence, severity, and relatedness of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), through Day 90, graded according to CTCAE
Number of participants with dose-limiting toxicities (DLTs)
时间窗: Day 1 through Day 21 after AAV administration
Incidence of protocol-defined dose-limiting toxicities (DLTs) within the 21-day DLT observation window following AAV administration
次要结局
- Number of participants with predefined clinically significant laboratory abnormalities(Day 1 through Day 90 after AAV administration)
- Number of participants with new-onset symptomatic heart failure or arrhythmias (CTCAE Grade ≥2)(Day 1 through Day 90 after AAV administration)
- Number of participants with injection site reactions(Day 1 through Day 90 after AAV administration)
- Number of participants who discontinue study treatment due to adverse events(Day 1 through Day 90 after AAV administration)