THE SCIENCE
Mitochondrial Repair is the Unaddressed Mechanism in AKI
Ischemia-reperfusion injury drives mitochondrial dysfunction in the kidney — loss of membrane potential, failure of ATP synthesis, and tubular cell death. MARY1's selective antagonism of 5HTR2B re-engages the PGC-1α–linked mitochondrial repair program, restoring mitochondrial biogenesis, fatty acid oxidation, and electron transport chain function in proximal tubule cells.
PREVENTIVE AND REPARATIVE ACTIVITY
Preclinical studies support MARY1 activity in two distinct windows: administered prior to anticipated ischemia-reperfusion injury, MARY1 reduces the severity of renal injury; administered after injury, it drives recovery. This dual-window profile has direct relevance to surgical settings where the injury window is known in advance. Additional IP covering the preventive use is in process.
VALIDATED ACROSS SPECIES AND MODELS
5HTR2B expression confirmed in rabbit and human renal proximal tubule cells, and mouse renal cortex. MARY1 yields reproducible efficacy signals across mouse and rat ischemia-reperfusion AKI, and AKI to CKD durability models — the core evidence base for our lead program and near term follow-ons with markers of injury, inflammation, and fibrosis correlating with improved kidney function recovery. Additional preclinical signals in chronic kidney disease, diabetic kidney disease, and aging kidney models point to a broader mitochondrial repair platform.
MEASURABLE PD BRIDGE TO HUMANS
PGC-1α, mitochondrial DNA, FAO and ETC proteins, and tubular injury and recovery signals are being developed as qualified clinical assays — designed to confirm mechanism engagement and recovery attribution in first-in-human studies.
CLASS AWARE SAFETY LOGIC
Known 5HTR2B valvulopathy risk is agonism-linked. MARY1 is a functional antagonist with no 5HTR2A/2C activity at tested concentrations. Rat 28-day tolerability preserved survival, body weight, and organ weight to 100× the therapeutic dose. The IND plan is designed to retire class risk prospectively.
PUBLISHED PRECLINICAL EVIDENCE
Discovery of a Novel, Potent, and Selective 5‑Hydroxytryptamine 2B Receptor Antagonist that Induces Mitochondrial Biogenesis in the Kidney
This mechanistic study shows that MARY1 induced PGC-1α signaling depends on 5HTR2B and PI3K/MEK linked pathway engagement, supporting a mechanistically grounded mitochondrial biogenesis thesis.
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MARY1 Restores Mitochondrial Homeostasis and Accelerates Renal Recovery Following Acute Kidney Injury
This in vivo study showed that in rodent AKI models, MARY1 increased mitochondrial biogenesis markers and improved renal function during early recovery.
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