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.
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
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
Sequential
AAV9-Follistatin gene therapy
GeneticOne-time intramuscular administration of an adeno-associated virus, serotype 9, (AAV9) vector encoding human follistatin.
VEGF Plasmid
GeneticIntramuscular supercoiled plasmid DNA gene therapy encoding vascular endothelial growth factor (VEGF).
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
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
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
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)
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)
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)
Change from baseline in Appendicular Lean Mass Index (ALMI) measured by DXA
Change from baseline in Appendicular Lean Mass Index (ALMI) measured by dual-energy X-ray absorptiometry (DXA)
Change from baseline in Bone Mineral Density (BMD) measured by DXA (g/cm²)
Change from baseline in bone mineral density (BMD) measured by dual-energy X-ray absorptiometry (DXA)
Change from baseline in lower limb one-repetition maximum (1RM) strength (kg)
Change from baseline in maximal voluntary strength assessed by one-repetition maximum (1RM) testing, assessed using leg press 1RM testing
Change from baseline in grip strength (kg)
Change from baseline in maximal grip strength (kg), assessed using standardized hand dynamometry
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Unlimited Biotechnology LLC
Lead sponsor
Global Alliance for Regenerative Medicine
Collaborator