Abstract
Purpose :
AMD is a common cause of the vision loss in elderly. There is no treatment for the most prevalent dry form of AMD. Transthyretin (TTR) Amyloid Cardiomyopathy (ATTRwt-CM) is caused by aggregation of wild-type TTR. It affects over 25% of individuals over the age of 80. The high rate of comorbidity between dry AMD and ATTRwt-CM is expected based on the high population frequency of both conditions. We characterized ACPHS-52, a bispecific RBP4/TTR ligand, as a new therapy that can be used for treating the dry AMD/ ATTRwt-CM comorbidity.
Methods :
Binding assays were used to measure binding potency for RBP4 and TTR. Serum RBP4 dynamics in mice was assessed with the ELISA assay. Retinal bisretinoids in Abca4-/- mice were quantified using HPLC. TTR tetramer stabilization was studied using acid-induced and thermal TTR aggregation protocols.
Results :
In addition to good binding potency against RBP4 and TTR, ACPHS-52 induces sustained serum RBP4 reduction in mice upon chronic dosing and robustly inhibits bisretinoid accumulation in the Abca4-/- mouse model of enhanced retinal lipofuscinogenesis. The compound does not inhibit the visual retinoid cycle in mice, as can be judged from the unchanged rate of ERG a- and b-wave amplitudes recovery after photobleaching. The compound stabilizes TTR tetramers indicating that it can prevent amyloidogenic TTR aggregation that leads to ATTRwt-CM
Conclusions :
Bispecific compounds like ACPHS-52 can be used for treating macular degeneration associated with lipofuscin accumulation in patients who may be predisposed to TTR amyloidosis.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.