Catalytic Photooxygenation Demonstrates Therapeutic Efficacy in Transthyretin Amyloidosis

Abstract

The escalating global trend of aging populations has brought attention to the rising prevalence of late-onset amyloid disorders. Among them, amyloid transthyretin (ATTR) amyloidosis presents a growing area of unmet medical needs. While current treatment modalities have demonstrated efficacy in preventing or delaying amyloid generation, methodology to selectively modify and neutralize existing amyloid burdens remains inadequately addressed, leaving the fundamental irreversibility and hence the fatality of these conditions, a long-standing medical challenge. Here, we report the first demonstration of therapeutic efficacy in ATTR amyloidosis via dynamic control of ATTR aggregation and toxicity, enabled by small-molecule organophotocatalysis. Selective incorporation of hydrophilic oxygen atoms into the hydrophobic amyloid core reshapes the aggregation landscape, neutralizing proteotoxicity, and mitigating cellular damage. Additionally, this targeted covalent modification significantly reduces in vivo ROS levels, correlating with the observed therapeutic effects in Caenorhabditis elegans, the only experimental model replicating key clinical manifestations of the disease. Docking simulations elucidated the molecular basis of catalyst performance, providing the foundational blueprint for amyloid-neutralizing organophotocatalysis. Collectively, this study provides a scalable approach to overcoming a persistent barrier in amyloidosis therapy.