The devastating effects of rare disorders are no more felt than those suffering from the autosomal dominant genetic disease commonly referred to as progeria—formally known as Hutchinson-Gilford progeria syndrome (HGPS)—which is characterized by premature aging. Now, investigators from the University of Cambridge have identified a potential therapeutic target, which they have shown leads to significant health and lifespan gains in a mouse model of HGPS. Findings from the new study were published recently in Nature Communications, in an article entitled “Targeting of NAT10 Enhances Healthspan in a Mouse Model of Human Accelerated Aging Syndrome.”

HGPS is a rare condition in which patients have an average life expectancy of around 15 years, suffering a variety of symptoms, including short stature, low body weight, hair loss, skin thickening, problems with fat storage, osteoporosis, and cardiovascular disease—and often dying of a heart attack.

By screening candidate molecules for an effect on nuclear membranes in human HGPS patient-derived cells in vitro, the authors previously identified a small molecule called Remodelin as an effective ameliorative agent. They then identified which component of the cells was being affected by Remodelin—an enzyme with a variety of cell functions, called N-acetyltransferase 10 (NAT10).

“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),” the authors wrote. “Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a LmnaG609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS.”

“We're very excited by the possibility that drugs targeting NAT10 may, in future, be tested on people suffering from HGPS,” explained senior study investigator Steve Jackson, Ph.D., professor of biology in The Gurdon Institute at the University of Cambridge. “I like to describe this approach as a rebalancing toward the healthy state.”

In the current study, the researchers sought to take these findings into a mouse model with the same genetic defect as HGPS patients, to see whether inhibiting NAT10—either chemically by administration of Remodelin or genetically by engineering reduced production of NAT10—could ameliorate the disease. The results show that these approaches indeed significantly improved the health of the diseased mice, increased their lifespan, and reduced the effects of the HGPS mutation across a variety of measures in body tissues and at the cellular level.  

“We first studied the cell biology to understand how the disease affects cells, and then used those findings to identify ways to rebalance the defect at the whole-organism level.” Dr. Jackson concluded. “Our findings in mice suggest a therapeutic approach to HGPS and other premature aging diseases.”