Abstract
Purpose :
Subretinal neovascularization is a characteristic of type 3 wet age-related macular degeneration (AMD). Vldlr-/- mice exhibit subretinal neovascular lesions. Retinal microglia play a critical role in regulating neovascularization in Vldlr-/- mice. D-4517.2 is a new precision nanomedicine technology that inhibits vascular endothelial growth factor (VEGF) receptor tyrosine kinases selectively in reactive microglia and hypertrophic retinal pigment epithelial (RPE) cells. The precision nanomedicine technology is based on hydroxyl dendrimers (HDs). The purpose of this study was to evaluate the cellular localization and efficacy of D-4517.2 in this mouse model.
Methods :
HDs covalently conjugated to Cy5 (D-Cy5) and D-4517.2 were provided by Ashvattha Therapeutics. Vldlr-/- mice were fed a diet rich in fat and protein to reduce biological variability of the neovascular phenotype. Vldlr-/- pups received two subcutaneous injections of D-Cy5, one at P14 and one at P21, with littermates as PBS control. Localization of D-Cy5 was assessed by cryosection and retinal flatmounts at P28. Microglia/macrophages were localized with Iba1 staining. D-4517.2 was administered systemically, either by subcutaneous injection (0.5 mg/kg or 2 mg/kg) or oral gavage (50 mg/kg or 250 mg/kg). D-4517.2 was administered systemically every other day from P14 to P34, with saline control littermates. At P35, mice were sacrificed, and retinal flatmounts prepared for quantitation of number of neovascular lesions.
Results :
At P28, Iba1+ cells were found in close association with neovascular lesions. D-Cy5 colocalized with Iba1+ cells (microglia, macrophages) associated with neovascular lesions and in the choroid. Both low and high subcutaneous doses of D-4517.2 significantly decreased the number of neovascular lesions, compared to saline control (low: n=12, p=0.031, high: n=16, p=0.016). Similarly, high doses of oral D-4517.2 significantly decreased the number of neovascular lesions (n=16, p= 0.016).
Conclusions :
Systemic administration of D-4517.2 provides an approach for selective cellular targeting in the retina and choroid, especially microglia/macrophages. The beneficial effect of D-4517.2 indicates the value of targeting microglia/macrophages and supports the development of this drug as a systemic treatment for wet AMD.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.