Results of the first-ever clinical drug trial for children with Progeria, a rare, fatal “rapid-aging” disease, demonstrate the efficacy of a farnesyltransferase inhibitor (FTI), a drug originally developed to treat cancer. The clinical trial results, completed only six years after scientists identified the cause of Progeria, included significant improvements in weight gain, bone structure and, most importantly, the cardiovascular system, according to The Progeria Research Foundation (PRF) and Boston Children’s Hospital.

These results were published in Proceedings of the National Academy of Sciences.

Progeria, also known as Hutchinson-Gilford Progeria Syndrome (HGPS), is a rare, fatal genetic disease characterized by an appearance of accelerated ageing in children. All children with Progeria die of the same heart disease that affects millions of normal ageing adults (atherosclerosis), but instead of occurring at 60 or 70 years of age, these children may suffer heart attacks and strokes as early as age five years, with the average age of death at 13 years.

“To discover that some aspects of damage to the blood vessels in Progeria can not only be slowed by the FTI called lonafarnib, but even partially reversed within just 2.5 years of treatment is a tremendous breakthrough, because cardiovascular disease is the ultimate cause of death in children with Progeria,” said Leslie Gordon, MD, PhD, lead author of the study, medical director for PRF, and mother of a child with Progeria. In addition, Dr Gordon is a staff scientist at Boston Children’s Hospital and Harvard Medical School, and associate professor at Hasbro Children’s Hospital and Alpert Medical School of Brown University.

Twenty-eight children from 16 countries participated in the two-and-a-half year drug trial, representing 75 per cent of known Progeria cases worldwide at the time the trial began. Of those, 26 are children with the classic form of Progeria. The children travelled to Boston every four months to receive comprehensive medical testing through Boston Children’s Hospital’s Clinical and Translational Study Unit.

Treatment consisted of the FTI lonafarnib, supplied by Merck & Co., given to children orally, twice-a-day over the course of the study, under the supervision of principal investigator Mark Kieran, MD, Ph.D., director of paediatric medical neuro-oncology at the Dana-Farber/Children’s Hospital Cancer Centre.

The research team, which included specialists at Boston Children’s Hospital, Brigham & Women’s Hospital and Dana-Farber Cancer Institute, evaluated the children’s rate of weight gain compared to their pre-therapy rate as the primary outcome because children with Progeria experience severe failure to thrive, and have a consistent, very slow linear rate of weight gain over time. Researchers also examined arterial stiffness (a predictor of heart attack and stroke in the general population), bone density and rigidity (indicators of osteoporosis). Every child completing the study showed improvement in an ability to gain additional weight, increased flexibility of blood vessels or improved bone structure.

Results included improvement in one or more of the following areas:

One in three children demonstrated a greater than 50 per cent increase in annual rate of weight gain or switched from weight loss to weight gain, due to increased muscle and bone mass.

On average, skeletal rigidity (which was highly abnormal at trial initiation) improved to normal levels after FTI treatment.

Arterial stiffness, strongly associated with atherosclerosis in the general ageing population, decreased by 35 per cent. Vessel wall density also improved with treatment.

Following the 2003 discovery of the gene that causes Progeria, researchers identified FTIs as a potential drug treatment for Progeria. Children with Progeria have a genetic mutation that leads to the production of the protein progerin, which is responsible for Progeria. Progerin blocks normal cell function and part of its toxic effect on the body is caused by a molecule called a “farnesyl group,” which attaches to the progerin protein. FTIs act by blocking the attachment of the farnesyl group onto progerin.

“In the early stages of planning for this clinical trial, we realized that my team’s experience using FTIs to treat children with brain cancer could bring together PRF’s preclinical research efforts and the expertise we needed to study the drug in children with Progeria,” said Kieran, the study’s senior author and associate professor of Pediatrics at Harvard Medical School. Dr Kieran further added, “The premise behind studying this drug was that by stopping the attachment of the farnesyl group onto progerin in children with Progeria, progerin may be inactivated, reducing some effects of the disease.”

“PRF provides a model for disease research organizations, and is a good example of successful translational research, moving from gene discovery to clinical treatment at an unprecedented pace,” added Dr Kieran.

PRF and its scientific partners have identified the genetic mutation that causes the disease, funded preclinical research and funded clinical trials. A second clinical trial, funded by the National Institutes of Health (NIH) and PRF, is currently underway and more trials are expected to follow.

“The partnership between PRF, the research team and these courageous families was essential for success,” said Dr Gordon. “It required identifying children and their home doctors from around the globe, obtaining the essential pre-trial clinical information, transporting families to and from Boston, supplying translators both inside and outside of the hospital setting, and putting together a multidisciplinary clinical team to assess treatment effects. But it was all worth it, and I believe we have set in motion a blueprint for successful treatment trials for children with Progeria and for other rare diseases.”

“The results of this study provide our family with excitement and hope for Megan’s future,” said Sandy Nighbor, mother of Megan, a 12-year-old child who participated in the clinical trial. “We’re grateful to The Progeria Research Foundation and all of the doctors for their commitment to helping my daughter and all children with Progeria.”

Previous research shows that progerin is also produced in the general population and increases in the body with age. A number of studies successfully linked progerin with normal ageing, including a causal link between progerin and genetic instability, specifically telomere dysfunction in the aging process. Researchers plan to continue researching the effect of FTIs, which may help scientists learn more about cardiovascular disease that affects millions, as well as the normal ageing process.

“One of the main reasons we achieved breakthrough results in this first trial is because of the tremendous supporters who provided funding, and helped get us one step closer to achieving our ultimate goal – a cure for Progeria,” said Audrey Gordon, executive director of PRF. “Every donation makes a difference. With continued support, we will fund research that will not only allow children with Progeria around the world to live long and healthy lives, but may also advance our understanding of the normal ageing process that affects us all.”

The PRF is currently funding a clinical trial in which children with Progeria receive FTI plus two additional medications to slow the progression of Progeria and continues to identify more children who can benefit from the programmes and services that it provides while helping advance research towards treatment and cure.

Boston Children’s Hospital is home to the world’s largest research enterprise based at a paediatric medical centre, where its discoveries have benefited both children and adults.