IF a single systemically administered Proteo-Lipid Vehicle (PLV) encoding a dual logic-gated payload — (1) a p16^INK4a promoter-driven inducible Caspase-9 (iCasp9) senolytic module AND (2) a Muscle Creatine Kinase (MCK) promoter-driven FST344 anabolic module — is delivered intravenously (estimated 1–3 mg/kg pDNA equivalent, repeat-dosed at 4-week intervals) to aged (22–24-month-old) male and female C57BL/6J mice with established sarcopenia,

THEN gastrocnemius and tibialis anterior muscle mass (g), cross-sectional area (CSA, µm²), grip strength (gf/g body weight), and satellite cell pool size (Pax7+ cells/fiber) will be significantly greater — estimated 25–40% improvement over vehicle — than in cohorts receiving either the senolytic module alone, the FST344 module alone, or an equivalent-dose single-isoform AAV1-FST344 (positive control), with the combination outperforming each monotherapy by a margin detectable at 12 weeks post-treatment initiation,

BECAUSE the following mechanistic cascade operates:

1. Senescent cell clearance via p16-iCasp9: Aged skeletal muscle harbors an accumulation of p16^INK4a-expressing senescent satellite cells and fibro-adipogenic progenitors (FAPs). The PLV's FAST-protein-mediated direct membrane fusion deposits the iCasp9 plasmid into the cytoplasm of all transduced cells, but iCasp9 protein is expressed only where the p16^INK4a promoter is transcriptionally active — selectively triggering apoptosis in senescent cells while sparing quiescent or actively cycling cells. (Oisin's platform delivers a non-integrating DNA plasmid encoding an inducible caspase-9 suicide gene under the control of a p16 promoter)[Oisin Biotechnologies, OncoSenX and SENSOlytics Platform Data, as cited in Evidence Set]

2. SASP suppression and niche decontamination: Upon senescent cell elimination, the local SASP is attenuated. Critically, aged-muscle SASP is enriched in activin A, IL-6, and TNF-α. Activin A — a TGF-β superfamily member — acts on ActRIIB to phosphorylate Smad2/3 in neighboring satellite cells, blocking their proliferative activation and self-renewal. (These senescent cells secrete proinflammatory cytokines, proteases, and growth factors — the SASP — which disrupt the local niche and impair the regenerative capacity of remaining healthy stem cells)[Chang et al., Nature Medicine, 2016, as cited in Evidence Set]

3. MCK-FST344 expression creates a targeted follistatin sink for dual ligand neutralization: Simultaneously, the MCK promoter drives FST344 expression specifically within skeletal muscle fibers, producing a locally concentrated follistatin protein that acts as a high-affinity ligand trap for both myostatin (GDF-8) and residual SASP-derived activin A circulating in the muscle interstitium. (FST acts as a high-affinity ligand trap; it binds circulating myostatin and activin, thereby preventing these ligands from interacting with the Activin Type IIB receptor on the muscle fiber membrane)[Al-Zaidy et ...

SENS category: GlycoSENS