IF UDP-003 (50 mg/kg, twice-weekly, subcutaneous injection for 12 weeks) is co-administered with oral trehalose (2% w/v in drinking water ad libitum) — a disaccharide known to activate TFEB-driven lysosomal biogenesis independently of mTORC1 suppression — to aged (≥52-week-old) male ApoE-/- mice with established Western-diet atherosclerosis,

THEN aortic root plaque area will be reduced by ≥40% relative to vehicle control (vs. an estimated ≤30% for UDP-003 monotherapy at the same dose), with a disproportionate and independently significant reduction in necrotic core fraction (≥50% reduction in acellular necrotic area as a percentage of total plaque area, measured by H&E cross-section morphometry at the aortic root at 12 weeks), and a ≥60% restoration of ex vivo macrophage efferocytotic index relative to young reference animals,

BECAUSE the following sequential and synergistic mechanistic chain operates:

1. 7-ketocholesterol (7KC) accumulates preferentially in macrophage lysosomes within established atherosclerotic plaques, causing lysosomal membrane permeabilization and blocking the nuclear translocation of Transcription Factor EB (TFEB) — the master regulator of lysosomal biogenesis and autophagy — thereby trapping macrophages in a dysfunctional, senescent foam cell state with suppressed phagocytosis and efferocytosis (Foam cell reversal and macrophage dysfunction cited in evidence set)[https://lifespan.io/news/rejuvenating-atherosclerotic-foam-cells/]

2. UDP-003, a computationally designed cyclodextrin dimer engineered with a cavity that selectively accommodates the 7-ketone moiety of 7KC, penetrates atherosclerotic lesions and encapsulates intracellular 7KC with high affinity, solubilizing the oxysterol for renal excretion and restoring lysosomal membrane integrity, partially reversing foam cell phenotype and restoring phagocytosis and efferocytosis (UDP-003 preclinical efficacy: 7KC clearance, foam cell reversal, urinary excretion demonstrated in vivo)[https://longevity.technology/news/new-data-supports-cyclaritys-approach-to-atherosclerosis-reversal/]

3. [SPECULATIVE] However, UDP-003 monotherapy alone cannot fully rehabilitate the TFEB transcriptional axis, because chronic 7KC exposure induces epigenetic silencing of TFEB target genes (including LAMP1, CTSB, NPC1, and MCOLN1) and sustained mTORC1 hyperactivation at the lysosomal surface — both of which persist after oxysterol extraction, creating a "transcriptional debt" that limits the speed and completeness of lysosomal biogenesis recovery even once 7KC is removed.

4. Trehalose, administered concurrently, activates TFEB nuclear translocation through an mTORC1-independent mechanism — proposed to involve direct inhibition of lysosomal mTORC1 docking via RAGULATOR complex interference — upregulating the full suite of lysosomal biogenesis genes in parallel with UDP-003's oxysterol extraction, ensuring that newly cleared macrophages have the lysosomal capacity to p...

SENS category: LysoSENS