Priming aged atherosclerotic macrophages with a single low-dose HPβCD injection to liquefy crystalline lysosomal 7-KC...

IF a sequential, two-phase lysosomal oxysterol clearance protocol — comprising a priming dose of low-dose hydroxypropyl-β-cyclodextrin (HPβCD; 500 mg/kg i.p., single dose, aggregate dissolution phase) followed 48 hours later by a sustained course of UDP-003 (cyclodextrin dimer; dose per ACTRN12623000768606 Phase 1 pharmacokinetics, i.p. or i.v., targeted extraction phase; 8 weeks) — is administered to aged (52-week-old, female, Western-diet-fed) ApoE−/− mice with established atherosclerosis,

THEN atherosclerotic plaque burden (en face Oil Red O, aortic root cross-section) will be reduced by ≥40% relative to either monotherapy alone, lysosomal membrane integrity in plaque macrophages (LysoTracker/Galectin-3 puncta) will normalize to levels observed in young ApoE−/− mice, foam cell frequency in aortic lesions (CD68+/filipin+ by immunofluorescence) will decrease by ≥50%, circulating 7-ketocholesterol (7-KC) will show a transient spike within 72 hours of HPβCD priming followed by sustained reduction below baseline after UDP-003 treatment, and macrophage efferocytosis capacity (dead cell clearance in ex vivo assay) will recover,

BECAUSE the following causal chain operates:

1. In aged ApoE−/− mice with advanced atherosclerosis, intraluminal 7-KC and 7β-hydroxycholesterol within macrophage lysosomes exist predominantly in a crystalline/aggregated physical state — densely packed lipid aggregates that are sterically inaccessible to the UDP-003 binding cavity despite its high molecular affinity for monomeric 7-KC. This physical-state barrier is the critical bottleneck that single-agent UDP-003 has not been optimized to overcome. (UDP-003 targets monomeric 7-KC encapsulation via its cyclodextrin dimer cavity)(WO2019/060839A1)

2. A single low-dose HPβCD priming injection exploits HPβCD's established capacity to dissolve cholesterol crystals and lysosomal lipid aggregates — demonstrated in ApoE−/− preclinical models where HPβCD reduced plaque burden via crystal dissolution — converting crystalline 7-KC into a soluble, monomeric form accessible to downstream UDP-003 encapsulation. (HPβCD dissolves lysosomal cholesterol crystals in ApoE-KO mice)(Zimmer et al., 2016, referenced in Evidence Set)

3. By using HPβCD at a single, low priming dose (well below the sustained dosing regimens that caused ototoxicity and pulmonary toxicity in chronic NPC protocols), the non-specific extraction of beneficial membrane cholesterol and dose-dependent toxicity are avoided; HPβCD's role is time-limited to aggregate liquefaction rather than sustained cholesterol depletion. (HPβCD at high sustained doses causes ototoxicity and indiscriminate membrane cholesterol stripping)(NCT02534844 / adrabetadex program, Evidence Set)

4. Following the 48-hour dissolution window, UDP-003 — a computationally engineered cyclodextrin dimer with structural selectivity for 7-KC over native cholesterol — encapsulates the now-solubilized oxysterol within the lysosomal compartment (reached via...

SENS category: GlycoSENS