Abstract Body: Introduction: Cerebral amyloid angiopathy (CAA) is characterized by amyloid beta (Aβ) accumulation in cerebral vascular walls, leading to structural and functional alterations that often result in cerebral microbleeds (CMBs), hemorrhagic strokes, and cognitive decline. Current therapies focus on managing symptoms and minimizing risk factors for cerebrovascular events; no disease-modifying treatments are available. Mivelsiran is an investigational, first-in-class RNA interference (RNAi) therapeutic whose mechanism of action reduces production of the amyloid beta precursor protein (APP) upstream of Aβ. In this study, we hypothesized that using small interfering RNA (siRNA) to lower APP in rodent models of Aβ-related pathology would reduce the accumulation of Aβ and the incidence of CMBs.
Methods: A bigenic (APPSwDI/Nos2^-/-) mouse model of Alzheimer’s disease that develops high levels of vascular amyloid and a transgenic rat model (rTg-DI) of capillary CAA were used. A single dose of APP-lowering siRNA or artificial cerebrospinal fluid was assessed post-dose (p.d.). Immunohistochemical staining of brain tissue assessed Aβ accumulation. Hemosiderin staining identified CMBs in the rat model only; CMBs do not typically occur in the mouse model.
Results: Compared with controls, mice receiving APP-targeting siRNA had 45.6% and 45.5% lower mean Aβ accumulation in the hippocampus 3 and 6 months p.d. (7–11 animals/group, p<0.05), and rats had an 83.4% mean ipsilateral reduction in Aβ accumulation in the parenchyma (4–10 animals/group, p<0.01) 6 months p.d. Similarly, mean Aβ vascular accumulation was reduced by 60.2% and 55.6% in the mouse model (p<0.05) 3 and 6 months p.d. and by 81.2% in the rat model (p<0.01) 6 months p.d. In the rat model, we observed a 69.3% (p<0.05) mean reduction in CMB occurrence (number of CMBs per cluster), and CMB size (mean area, p<0.01) was 69.1% lower in each bleed cluster (6–16 total bleed clusters analyzed).
Conclusions: Lowering APP production with siRNA in models of Aβ overproduction significantly reduced vascular amyloid burden, and CMB occurrence and size. These results provide the first preclinical evidence to support the rationale that lowering APP with an RNAi therapeutic could slow or halt the progression of CAA. A proof-of-concept Phase 2 study (cAPPricorn-1) has been initiated to assess the efficacy and safety of mivelsiran in patients with CAA.