Progeria Treatment Within Reach? Drug May Target Accelerated Aging Enzyme in Children
Progeria, a fatal disorder that causes accelerated aging in children, has captured widespread attention with the presence of public figures like Adalia Rose, Hayley Okines, and Leon Botha.
Also known as Hutchinson-Gilford Progeria Syndrome, the genetic condition is extremely rare—only one in 8 million children develop it, and as few as 200 cases may exist worldwide. No proven progeria treatment exists yet, and its trajectory is dramatic. The average age of death is 13 years, usually from progressive cardiovascular disease that leads to heart attack or stroke.
Last year, scientists found that an experimental cancer drug called Lonafarnib showed promise as a progeria treatment, promoting weight gain and improving symptoms like low bone density and arterial stiffness. Some researchers, however, were skeptical of the drug's efficacy, and additional trials are underway.
Now, researchers from the Sahlgrenska Academy at the University of Gothenburg in Sweden have identified a mechanism that blocks an enzyme associated with accelerated aging. Their findings were published today in the journal Science.
"This study is a breakthrough for our research group after years of work," said senior author Martin Bergö in a news release. "When we reduce the production of the enzyme in mice, the development of all the clinical symptoms of progeria is reduced or blocked."
The research may lead to enzyme inhibitor drugs that are effective as progeria treatments in humans as they are in mice.
Treating Prematurely Accelerated Aging in Mice
Progeria is caused by a spontaneous genetic mutation, which means it is not inherited from parents.
The mutation occurs in a gene that encodes the proteins prelamin A and lamin C, say the researchers, resulting in an abnormal form of prelamin A called progerin that builds up in the membrane surrounding the cell nucleus. That causes deformations in the shape of the nucleus, leading to a cascade of cellular events that cause typical progeria symptoms.
Bergö's team targeted an enzyme called isoprenylcysteine carboxyl methyltransferase (ICMT), which alters prelamin A by attaching a small chemical group to its tail end in a process called methylation.
They bred a mouse model of progeria, in which genetically altered mice developed hair loss, a stilted gait, reduced strength, and had lifespans of only about 10 weeks instead of the standard two years.
By blocking the ICMT enzyme, they prevented the methylation of prelamin A. That delayed the aging of cells called fibroblasts, which are related to the development of progeria, suggesting a potential treatment.
"We have also studied cultured cells from children with progeria, and can see that when the [ICMT] enzyme is inhibited, the growth of the cells increases by the same mechanism as in mouse cells," said Bergö in his statement.
Future Directions for Progeria Treatment
The next step is to test drugs that block the ICMT enzyme on mice with progeria.
Bergö says that his team at the Sahlgrenska Academy is collaborating on an experimental trial with researchers in Singapore, who have developed candidate ICMT inhibitor drugs.
However, it will likely be some years before they can prove the drugs' efficacy in human progeria treatment. Clinical trials are time-consuming, and the drugs need to be proven in mice before they can be tested in humans.
In the meantime, Bergö is also studying how ICMT inhibition affects normal aging in mice. He suggests that the research may lead to insights about normal human aging.
Children with progeria develop hallmark symptoms of aging like hair loss, short stature, osteoporosis, heart attack, stroke, and muscle weakness, but not dementia or cancer.
It's obvious why the public is so captivated by the condition, he said in the statement, because "the resemblance between progeria patients and normally-aged individuals is striking and it is tempting to speculate that progeria is a window into our normal aging process."
Source:
Mohamed X. Ibrahim, Volkan I. Sayin, Murali K. Akula, Meng Liu, Loren G. Fong, Stephen G. Young, and Martin O. Bergo. Targeting Isoprenylcysteine Methylation Ameliorates Disease in a Mouse Model of Progeria. Science, 16 May 2013.