Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome.

Abstract

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances cardiac function, fitness and healthspan in a LmnaG609G HGPS mouse model. Collectively, the data provided here highlight NAT10 as a potential therapeutic target for HGPS.