Age-related Muscle DeclinePhase 1/2CALM-AF-AINCT07443826

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

A Phase 1/2 study testing AAV9-Follistatin gene therapy and VEGF Plasmid in people with Age-related Muscle Decline, run by Unlimited Biotechnology LLC at 1 site in Honduras.

Recruiting

Looking for participants now. Contact the study team or a site below to ask about taking part.

Sites and contacts

Official record

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Trial summary

Who is it for?: Ages 35 to 75 yearsHealthy volunteers can take part
Conditions the study is for: Age-related Muscle Decline
What is being tested?: AAV9-Follistatin gene therapy and VEGF Plasmid
Type of treatment: Injection or infusion
Could I receive a placebo?: No, everyone receives an active treatment
How many people: 12 participants
Where: 1 siteHonduras
Study dates: 1 Jun 2026to 30 Jun 2028
Phase: Phase 1/2

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 35 to 75 years
All sexes
Healthy volunteers accepted
Adult, Older adult

Who may be able to join

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

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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)

Who cannot join

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:

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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
Neurodegenerative, neuromuscular, psychiatric, or movement disorders associated with functional or cognitive impairment (e.g., dementia, Parkinson's disease)
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
Exception: Transient CK elevation within 72 hours of strenuous exercise, intramuscular injections, or trauma is permitted if CK normalizes (≤1.0× ULN) on repeat testing before baseline visit
Systemic connective tissue diseases (CTDs), including:
Systemic lupus erythematosus (SLE), SLE overlap syndromes, or drug-induced SLE
Mixed connective tissue disease (MCTD)
Systemic sclerosis (SSc, scleroderma): diffuse, limited, or sine scleroderma
Inflammatory myopathies: polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), or overlap myositis
Primary Sjögren's syndrome requiring systemic immunosuppression (corticosteroids >10 mg/day prednisone equivalent, DMARDs, or biologics)
Rheumatoid arthritis with extra-articular manifestations or requiring biologic DMARDs
Undifferentiated connective tissue disease (UCTD) meeting ≥2 CTD classification criteria
Current or recent (within 3 months) use of immunosuppressive agents, including corticosteroids, cyclosporine, tacrolimus, methotrexate, cyclophosphamide, IVIG, or rituximab
Acute bacterial, fungal, or viral infection, fever, or receipt of live vaccines within 30 days prior to screening
Infectious disease exclusions, including:
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
Increased bleeding risk, including platelet count <100 ×10⁹/L, active anticoagulation (unless washout possible), or known coagulation disorders
Severe physical functional limitation (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

Trial locations and contacts

1 site in 1 country. Contact the study team or a site near you to ask about taking part.

Ivan Morgunov contact

+31623454906

ivan@unlimit.bio

Honduras1 site, 1 recruiting

GARM
Coxen Hole, Bay Islands, 34101
Mayra Hoch, +504-2408-3544, mayra@garmclinic.com
Recruiting

Other trials in Honduras

About this study

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.

Read the detailed description

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.

Screening (up to 7 days) includes medical history, physical examination, laboratory tests, and baseline muscle assessments (e.g., DXA, strength, and functional testing). The core study period lasts approximately 90 days (for Group 3 = 120 days), with frequent safety assessments and functional evaluations. Participants may opt into extended safety follow-up at approximately 6 and 12 months.

Participation involves potential risks, including:

Immune reactions to AAV or follistatin (e.g., flu-like symptoms, elevations in liver enzymes), monitored and managed per protocol;
Risks associated with VEGF plasmid (e.g., transient limb pain or swelling);
Adverse effects related to rapamycin (e.g., mucositis, metabolic changes, increased infection risk);
Unknown or rare risks inherent to gene therapy. Independent safety oversight and predefined stopping rules are in place.

Direct clinical benefit cannot be guaranteed. Participants may experience improvements in muscle mass, strength, endurance, or functional performance; however, this is an early-phase trial primarily designed to assess safety and feasibility. The study may contribute to the development of future therapies for age-related muscle decline.

Participants should anticipate approximately three months of active participation, with optional follow-up extending to 12 months.

Conditions: Age-related Muscle Decline
Being tested: AAV9-Follistatin gene therapy, VEGF Plasmid
Keywords: Sarcopenia, Muscle Atrophy, Skeletal Muscle, Muscle Weakness, Muscle Strength, Aging, Frailty, Follistatin, Myostatin, Viral Vectors, Adeno-Associated Viruses, Activins, Vascular Endothelial Growth Factor A, Angiogenesis Inducing Agents, Plasmids, Intramuscular Injections, Immunosuppression, Prednisolone, Sirolimus, Safety
Medical subject headings: Sarcopenia, Muscular Atrophy, Muscle Weakness, Frailty

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

AAV9-Follistatin gene therapyGenetic
One-time intramuscular administration of an adeno-associated virus, serotype 9, (AAV9) vector encoding human follistatin.
VEGF PlasmidGenetic
Intramuscular supercoiled plasmid DNA gene therapy encoding vascular endothelial growth factor (VEGF).

Study groups in NCT07443826
Study group	Role	What they receive
Low-Dose AAV-Follistatin Monotherapy	Experimental	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. Receives: Genetic: AAV9-Follistatin gene therapy
High-Dose AAV-Follistatin Monotherapy	Experimental	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. Receives: Genetic: AAV9-Follistatin gene therapy
Combination: AAV-Follistatin + VEGF Plasmid	Experimental	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. Receives: Genetic: AAV9-Follistatin gene therapy; Genetic: VEGF Plasmid

What is being measured

The primary outcome is the main question the study is designed to answer.

Number of participants with treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs)
Incidence, severity, and relatedness of treatment-emergent adverse events (TEAEs), including serious adverse events (SAEs), through Day 90, graded according to CTCAE
Measured: Day 1 through Day 90 after AAV administration
Number of participants with dose-limiting toxicities (DLTs)
Incidence of protocol-defined dose-limiting toxicities (DLTs) within the 21-day DLT observation window following AAV administration
Measured: Day 1 through Day 21 after AAV administration

Secondary outcomes (4)

Number of participants with predefined clinically significant laboratory abnormalities
Number of participants with any of the following laboratory abnormalities through Day 90 (Day 120 for Group 3):
ALT or AST >3× ULN; Total bilirubin >2× ULN; Serum cystatin C ≥1.5× baseline; eGFR decline ≥25% from baseline; Hemoglobin <120 g/L in men or <110 g/L in women; Hemoglobin decrease ≥2 g/dL; Platelet count <100 × 10⁹/L; Neutrophil count <1.5 × 10⁹/L; Creatine kinase ≥5× ULN
Measured: Day 1 through Day 90 after AAV administration
Number of participants with new-onset symptomatic heart failure or arrhythmias (CTCAE Grade ≥2)
Number of participants experiencing new-onset symptomatic heart failure or clinically significant arrhythmias graded ≥2 according to CTCAE v5.0 through Day 90 (Day 120 for Group 3)
Measured: Day 1 through Day 90 after AAV administration
Number of participants with injection site reactions
Number of participants experiencing injection site reactions (pain, swelling, erythema, induration, or local inflammation), graded according to CTCAE v5.0, through Day 90 (Day 120 for Group 3)
Measured: Day 1 through Day 90 after AAV administration
Number of participants who discontinue study treatment due to adverse events
Number of participants who discontinue study treatment due to adverse events through Day 90 (Day 120 for Group 3)
Measured: Day 1 through Day 90 after AAV administration

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

1 Jun 202630 Jun 2028

First posted2 Mar 2026
Study start1 Jun 2026
Primary completion30 Sep 2027 (estimated)
Study completion30 Jun 2028 (estimated)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Publications (11)Papers the sponsor has linked to this study.
Other trials for Age-related Muscle DeclineStudies of the same condition, open and under way.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 1/2
Primary purpose: Prevention
Allocation: Non-randomised
Intervention model: Sequential
Masking: None (open label)
Enrolment: 12 participants (estimated)

IDs, dates and publications

ClinicalTrials.gov ID: NCT07443826
Sponsor's protocol ID: UBL-CALMAF-001
Acronym: CALM-AF-AI
Status last verified: Jul 2026
First submitted: 4 Dec 2025
Last updated: 13 Jul 2026
Results posted: No
Data monitoring committee: No
FDA-regulated drug: No
FDA-regulated device: No
Individual data sharing: Undecided

Publications

Suoranta T, Laham-Karam N, Yla-Herttuala S. Strategies to improve safety profile of AAV vectors. Front Mol Med. 2022 Nov 1;2:1054069. doi: 10.3389/fmmed.2022.1054069. eCollection 2022.
PubMed 39086961
Tang R, Harasymowicz NS, Wu CL, Collins KH, Choi YR, Oswald SJ, Guilak F. Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity. Sci Adv. 2020 May 8;6(19):eaaz7492. doi: 10.1126/sciadv.aaz7492. eCollection 2020 May.
PubMed 32426485
Mendell JR, Sahenk Z, Al-Zaidy S, Rodino-Klapac LR, Lowes LP, Alfano LN, Berry K, Miller N, Yalvac M, Dvorchik I, Moore-Clingenpeel M, Flanigan KM, Church K, Shontz K, Curry C, Lewis S, McColly M, Hogan MJ, Kaspar BK. Follistatin Gene Therapy for Sporadic Inclusion Body Myositis Improves Functional Outcomes. Mol Ther. 2017 Apr 5;25(4):870-879. doi: 10.1016/j.ymthe.2017.02.015. Epub 2017 Mar 6.
PubMed 28279643
Nance ME, Shi R, Hakim CH, Wasala NB, Yue Y, Pan X, Zhang T, Robinson CA, Duan SX, Yao G, Yang NN, Chen SJ, Wagner KR, Gersbach CA, Duan D. AAV9 Edits Muscle Stem Cells in Normal and Dystrophic Adult Mice. Mol Ther. 2019 Sep 4;27(9):1568-1585. doi: 10.1016/j.ymthe.2019.06.012. Epub 2019 Jul 3.
PubMed 31327755
Al-Zaidy SA, Sahenk Z, Rodino-Klapac LR, Kaspar B, Mendell JR. Follistatin Gene Therapy Improves Ambulation in Becker Muscular Dystrophy. J Neuromuscul Dis. 2015 Sep 2;2(3):185-192. doi: 10.3233/JND-150083.
PubMed 27858738
Deev R, Plaksa I, Bozo I, Isaev A. Results of an International Postmarketing Surveillance Study of pl-VEGF165 Safety and Efficacy in 210 Patients with Peripheral Arterial Disease. Am J Cardiovasc Drugs. 2017 Jun;17(3):235-242. doi: 10.1007/s40256-016-0210-3.
PubMed 28050885
Deev R, Plaksa I, Bozo I, Mzhavanadze N, Suchkov I, Chervyakov Y, Staroverov I, Kalinin R, Isaev A. Results of 5-year follow-up study in patients with peripheral artery disease treated with PL-VEGF165 for intermittent claudication. Ther Adv Cardiovasc Dis. 2018 Sep;12(9):237-246. doi: 10.1177/1753944718786926. Epub 2018 Jul 11.
PubMed 29996720
Kota J, Handy CR, Haidet AM, Montgomery CL, Eagle A, Rodino-Klapac LR, Tucker D, Shilling CJ, Therlfall WR, Walker CM, Weisbrode SE, Janssen PM, Clark KR, Sahenk Z, Mendell JR, Kaspar BK. Follistatin gene delivery enhances muscle growth and strength in nonhuman primates. Sci Transl Med. 2009 Nov 11;1(6):6ra15. doi: 10.1126/scitranslmed.3000112.
PubMed 20368179
Mendell JR, Sahenk Z, Malik V, Gomez AM, Flanigan KM, Lowes LP, Alfano LN, Berry K, Meadows E, Lewis S, Braun L, Shontz K, Rouhana M, Clark KR, Rosales XQ, Al-Zaidy S, Govoni A, Rodino-Klapac LR, Hogan MJ, Kaspar BK. A phase 1/2a follistatin gene therapy trial for becker muscular dystrophy. Mol Ther. 2015 Jan;23(1):192-201. doi: 10.1038/mt.2014.200. Epub 2014 Oct 17.
PubMed 25322757
Giesige CR, Wallace LM, Heller KN, Eidahl JO, Saad NY, Fowler AM, Pyne NK, Al-Kharsan M, Rashnonejad A, Chermahini GA, Domire JS, Mukweyi D, Garwick-Coppens SE, Guckes SM, McLaughlin KJ, Meyer K, Rodino-Klapac LR, Harper SQ. AAV-mediated follistatin gene therapy improves functional outcomes in the TIC-DUX4 mouse model of FSHD. JCI Insight. 2018 Nov 15;3(22):e123538. doi: 10.1172/jci.insight.123538.
PubMed 30429376
Iyer CC, Chugh D, Bobbili PJ, Iii AJB, Crum AE, Yi AF, Kaspar BK, Meyer KC, Burghes AHM, Arnold WD. Follistatin-induced muscle hypertrophy in aged mice improves neuromuscular junction innervation and function. Neurobiol Aging. 2021 Aug;104:32-41. doi: 10.1016/j.neurobiolaging.2021.03.005. Epub 2021 Mar 12.
PubMed 33964607