A team from the University of Cambridge has identified a potential therapeutic target to combat Hutchinson-Gilford Progeria Syndrome (HGPS), a disease characterized by premature aging.
Preclinical data demonstrated that the chemical inhibition or genetic deregulation of the enzyme N-acetyltransferase 10 (NAT10) leads to significant health and lifespan gains in a HGPS mouse model.
“We’re very excited by the possibility that drugs targeting NAT10 may, in future, be tested on people suffering from HGPS,” senior author professor Steve Jackson said in a statement. “I like to describe this approach as a ‘re-balancing towards the healthy state.’ We first studied the cell biology to understand how the disease affects cells, and then used those findings to identify ways to re-balance the defect at the whole-organism level. Our findings in mice suggest a therapeutic approach to HGPS and other premature ageing diseases.”
HGPS is a rare condition where patients only have a life expectancy of around 15 years. Symptoms include short stature, low body weight, hair loss, skin thickening, problems with fat storage, osteoporosis and cardiovascular disease, which typically cause patients to die of a heart attack.
The disease is caused by specific mutations in the gene for the protein Lamin A—leading to the production of a shorter, dysfunctional protein that accumulates in cells, particularly in the membranes surrounding the nucleus, causing the disorganization of chromatin, deregulated transcription, the accumulation of DNA damage and defective cell proliferation.
The researchers previously identified a small molecule called remodelin as an effective ameliorative agent, after screening candidate molecules for an effect on nuclear membranes in human HGPS patient-derived cells in vitro.
They then identified which component of the cells was being affected by remodelin, an enzyme with a variety of cell functions, called NAT10.
The goal of the current study was to take the previous findings into a mouse model with the same genetic defect as HGPS patients to see if inhibiting NAT10—either chemically by the administration of remodelin or genetically by engineering reduced production of NAT10—could ameliorate the disease.
The researchers found that the new approaches significantly improved the health of the mice inflicted with HGPS, increased their lifespan and reduced the effects of the HGPS mutation across a variety of measures in body tissues and at the cellular level.
The study was published in Nature Communications.