In 1886, the physician Jonathan Hutchinson examined a six-year-old patient who lacked hair and had the withered skin of an old man. Later, in 1897, the physician Hastings Gilford followed up on this same patient and examined a second one with a similar appearance and documented in photographs the progression of the condition that rapidly ages people who have it.

Today, this condition is known as Hutchinson-Gilford progeria syndrome, HGPS, or simply progeria. It is extremely rare afflicting just one in 20 million, but its affects are quite visible and deadly.

The term “progeria” is derived from Greek word “proger” meaning prematurely old. The manifestations include growth failure, loss of body fat and hair, aged-looking skin, stiff joints, hip dislocation, cardiovascular disease, and stroke. Children with the condition live on average to a little more than 14 and die from heart disease typically associated with old age. There are no approved drugs to treat the condition.

It would take 117 years from the time Hutchinson first described the condition in his six-year-old patient before a genetic mutation driving the disease would be identified. That discovery has led to a series of developments that should serve as a roadmap for rare disease organizations and researchers seeking treatment for other rare genetic disease. It’s also a reminder of important lessons about the value of rare disease research, and ways to capitalize on work already done to treat other diseases.

This week researchers at Boston Children’s Hospital and Brown University report in a study published in JAMA on how lonafarnib, a failed cancer drug, showed the potential to extend the life of people with progeria. In a study of 27 progeria patients treated with lonafarnib compared with a pool of 103 contemporaneous untreated patients, lonafarnib treated patients experienced a significantly lower mortality rate (3.7 percent vs 33.3 percent) after a median of 2.2 years of follow-up.

“This study published in JAMA shows evidence that we can begin to put the brakes on the rapid aging process for children with progeria,” said Leslie Gordon, co-founder and Medical Director for The Progeria Researcher Foundation, and lead author of the study. “These results provide new promise and optimism to the progeria community.”

The Progeria Research Foundation funded the study. In fact, the foundation has funded four clinical trials and hundreds of scientific studies aimed at discovering treatments and potentially a cure for the condition. Previous studies funded by the group had linked lonafarnib to improvements in clinical trial endpoints associated with atherosclerosis and stroke.

In 2006, the lab of now National Institutes of Health Director Francis Collins identified the cause of progeria as a mutation in the LMNA gene. This leads to the production of a mutated form of the lamin A protein, progerin. In patients with progeria, the mutated protein accumulates in cells and causes progressive damage to the membrane of the cells.

As researchers came to understand the mechanism of the disease, they turned their attention to farnesyltransferase inhibitors like lonafarnib as a potential way to treat it. Lonafarnib inhibits an enzyme that is involved in the biological pathway that leads to the production of mutated protein.

Though the findings in the latest study are compelling, lonafarnib is not a cure. As Fuki Marie Hisama and Junko Oshima, both of the Division of Medical Genetics at the Department of Medicine of the University of Washington, Seattle note in an editorial that accompanied the study, the treatment did not improve many of the symptoms associated with progeria, such as hair and hearing loss, joint stiffness, or insulin resistance.

There is much here that not only progeria patients, but rare disease patients should find encouraging.

It’s a reminder that even though a rare disease may affect a small population of patients, the study of rare diseases may point a way to treat more common ones. Hisama and Oshima note investigations into the mechanism and treatment of progeria may yield new insights into the treatment of age-related cardiovascular diseases.

It reinforces the viability of repurposing as a strategy to find new treatments for rare diseases. As Hisma and Oshima write, as the molecular mechanisms of a disease are understood, that can point to existing therapies that may act on a disease because of a drug’s known effects on a specific biological pathway.

It also shows the vital role patient organizations can play in driving research and bringing together various collaborators to advance the understanding of a condition and develop treatments.

“For numerous other rare diseases,” write Hisma and Oshima, “the example of [progeria] highlights the importance of a solid basic research foundation in understanding the disease, the vital role of patient registries and engagement of patients and families, the need to foster close, ongoing, multidisciplinary collaborations between scientists and clinicians, and support from governmental agencies.”

Rare disease patient groups shouldn’t just cheer the progress the Progeria Research Foundation has made, they should draw lessons from it and apply it to their own quests.

April 26, 2018
Photo: Sam Berns who died in 2014 from complications from progeria and his mother Leslie Gordon, co-founder and Medical Director for The Progeria Researcher Foundation, professor of pediatrics at the Warren Alpert Medical School of Brown University and Hasbro Children’s Hospital, and lead author on the JAMA study,

 

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