The U.S. Food and Drug Administration has approved a treatment that could give children more time with a rare genetic disease that causes premature aging.
Children with the disease, known as Hutchinson-Gilford progeria syndrome, or progeria soon, often die of heart failure, heart attack, or stroke when they are teenagers. Most children with the disorder die before the age of 15. The newly approved drug, called Zokinvy, is the first and only approved treatment for progeria and certain related syndromes, the FDA announced on Nov. 20.
In the clinical trials of 62 children who received the drug, Zokinvy increased their half-life by an average of about 3 months during the first three years of treatment, compared with another 81 children who did not take the drug in a separate study that collected their health data. . Monitoring of children who continued to receive Zokinvy up to the age of 11 showed that, on average, the children’s lives were extended by approximately 2.5 years.
"This is not a cure," warns Monica Kleinman, a pediatric critical care physician at Boston Children's Hospital who participated in the clinical trials. “We hope to extend the life they (children) have by slowing down the pace of the disease,” but, she says, the drug does not give children a normal life.
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It is estimated that there are between 350 and 400 children worldwide who have progeria. For these children, a single mutation in their genetic code alters their health (SN: 2/7/13). That mutation interferes with the gene responsible for making the lamin A protein, which helps keep cell nuclei together. Children with progeria end up with higher amounts of a defective protein called progerin, which is similar to lamina A but with an additional piece attached. This protein gets trapped in cell membranes and cannot be recycled to fresh proteins, causing cells to age prematurely and making blood vessels and connective tissue stiffer, Kleinman says.
Everyone makes some progerin and the body does more as it ages, Kleinman explains, but "children with progeria make a huge amount." Children usually appear normal at birth, but begin to show signs of the disease in their first two years of life. Throughout their lives, these children experience hair and body fat loss, joint stiffness, cardiovascular disease, and other symptoms of accelerated aging.
Zokinvy, manufactured by Eiger BioPharmaceuticals in Palo Alto, California, blocks some of that progerin production, reducing the amount that builds up in children’s cells. But the oral drug, taken as capsules, does not completely block production, she said, and the amount patients can receive is limited by the drug's side effects, which include vomiting, diarrhea and fatigue.
The drug is a “testament to the power of basic research,” says Tom Misteli, a cell biologist at the National Cancer Institute in Bethesda, Maryland, who did not participate in the work on the drug. Zokinvy relies on decades of research on many aspects of the lamin A protein, including the "seemingly esoteric chemical modification" that progerin forms, he said.
“No one studying this protein or modification could have expected it to become a drug target,” Misteli adds. But once the disease-causing gene was identified, researchers focused on the class of drugs that include Zokinvy as potential treatments.
With the new drug approval, the focus is now on testing additional drugs or therapeutics in combination with Zokinvy, Misteli says. This could help extend the life of children with progeria even further. Researchers are also investigating gene therapy approaches, with the goal of correcting the mutation that causes debilitating disease.