AT-02: Using a Pan-Amyloid Weapon to Clear Medin From the Aging Aorta
Medin is the most common amyloid in the human body — present in the aortic wall of over 97% of people past age 50. It physically intercalates with elastic fibers, fragments them, and drives arterial stiffening. Mfge8 C2 knockout mice that cannot produce medin maintain youthful aortic elasticity into old age. The damage is established. The question is whether we can remove it.
AT-02 (Attralus) is a recombinant anti-SAP fusion protein with a human IgG1 Fc domain, originally developed for systemic amyloidosis. SAP (Serum Amyloid P component) universally coats all amyloid fibrils regardless of precursor protein — including medin. AT-02 binds the SAP coating, then recruits macrophages via Fc receptor engagement to phagocytose and destroy the fibril. It has demonstrated clearance of AL and ATTR amyloid in preclinical models across liver, heart, and kidney.
Nobody has pointed it at the aorta.
The proposal: administer AT-02 (10–30 mg/kg IV, biweekly, 12 weeks) to 18–24 month old wild-type C57BL/6 mice with confirmed aortic medin burden. Measure medin clearance by Congo red birefringence and anti-MFG-E8 immunofluorescence. Assess functional repair via elastin fiber continuity (Hart's staining) and aortic pulse wave velocity.
Predicted outcomes: ≥40% reduction in aortic medin burden, measurable restoration of elastic fiber architecture, and significant reduction in pulse wave velocity compared to age-matched controls.
Falsification: if AT-02 achieves <15% medin reduction in aortic tissue despite confirmed systemic SAP engagement, then either SAP coating on medin fibrils is insufficient for Fc-mediated phagocytosis in the aortic media, or tissue-resident macrophages in the arterial wall cannot execute ADCP against wall-embedded aggregates — both would invalidate the approach.
SENS category: AmyloSENS — immunological clearance of extracellular amyloid from the vascular wall
Key references: • Medin causes elastic fiber disruption and aortic stiffness (doi.org/10.1073/pnas.2011133117) • Medin-specific antibody restores cerebrovascular function — Wagner et al., Nature 2022 • AT-02 pan-amyloid SAP-targeting mechanism — Wall et al., Theranostics 2018