Great News For The Progeria Community

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(PLoS Biology)

(PLoS Biology)

A repurposed drug that reverses some of the rapid-aging symptoms of Hutchinson-Gilford progeria syndrome also extends life, according to a new report in the journal Circulation. That’s terrific news.

The disease is exceedingly rare, affecting 1 in 4-8 million newborns. Prevalence is 1 in 18 million, reflecting the fact that average lifespan is only 14.6 years.

The effects of the drug on symptoms were announced in fall 2012. I was just starting this blog then, and two of my earliest posts dealt with the disease.
My first post, “Progress for Progeria,” was an interview with Francis Collins, MD, PhD, about how he worked with the founders of the Progeria Research Foundation, Scott Berns, MD and his wife Leslie Gordon, MD, PhD, who were parents to then 22-month-old Sam. He became quite well known in his short time here. He passed away at the age of 17 early this year, and was the subject of the HBO documentary Life According to Sam. Dr. Gordon, from Hasbro Children’s Hospital of Brown University and Boston Children’s Hospital and medical director of the PRF, is first author of the new paper.

The drug lonafarnib alters the morphology (lower right) of the nuclei in cells from  children with progeria. (PLoS Biology)

The drug lonafarnib alters the morphology (lower right) of the nuclear membranes in cells from children with progeria. (PLoS Biology)

BASIC RESEARCH AND CONVERGING PATHWAYS
The progeria story is a beautiful cascade of discovery.

The work of the PRF led to finding mutations in the lamin A gene that cause progeria, and that revealed the mechanism, which in turn led to realization that a shelved pediatric cancer drug, lonafarnib, targeted the same pathway. Would it work against progeria? My second post, “From Rapid Aging to Common Heart Disease,” chronicled that story.

The short version: A class of drugs called farnesyl transferase inhibitors would remove a small organic molecule, farnesyl, from one end of lamin A protein. The problem behind progeria is that farnesyl groups aren’t removed, as they should be, due to mutation affecting a splice site that would otherwise enable the group to be jettisoned. The result is a version of the protein called progerin.

Normally lamin A forms part of the scaffolding that hugs the inner face of the nuclear membrane, contacting the threads of DNA and their associated proteins (chromatin) in the nucleus. With the farnesyl groups tenaciously hanging on, the altered architecture interferes with the chromatin, a little like poking one’s abdomen and jostling the intestines.

Effects are profound. Progerin impacts DNA replication, RNA transcription, chromatin formation, cell division, apoptosis, and formation of the pores that let molecules in and out of the nucleus. It’s little wonder that a suite of symptoms ensue, the aging connection emerging perhaps as the misshapen nuclear membrane touches the telomeres (chromosome tips), somehow accelerating the shrinkage that marks biological time.

Megan and Devin have progeria. (Progeria Research Foundation)

Megan and Devin have progeria. (Progeria Research Foundation)

NATURAL HISTORY INFORMS CLINICAL TRIALS
The early results reported in 2012 were incremental, yet definitely steps in the right direction. Some children gained weight faster, their arteries grew thinner and more elastic, and their bones strengthened and hearing improved. And now that a few more years have passed, it’s clear that the drug is also extending the short lives of these children and adolescents.

The new study underscores the importance of knowing the natural history of a disease – what happens, when, and for how long. The PRF patient registry identified 204 children, and information on them provided the control information to compare to effects on children given the drug. The researchers also consulted reports in the literature and databases to identify children to match with those being treated.

The trial began in 2007 with 28 children from 13 countries, and at first evaluated only lonafarnib. Two years later the protocol added a statin (pravastatin) and an osteoporosis drug (zoledronate), with funding from PRF and the National Heart, Lung and Blood Institute. These two drugs are also farnesylation inhibitors but complement lonafarnib in action. The investigators hypothesize that the lonafarnib is extending life because of its effects on arteries. The trial grew.

(NHGRI)

(NHGRI)

Results reported in the Circulation paper are striking. Among 43 treated children over the 6 years of the study so far, 5 died (11.6%). Among 43 in the “matched comparison group,” 21 died (48.8%).

Mean survival was extended 1.6 years in the treated kids. And that might be an underestimate, because many started the drug when they were far along. Treating earlier might extend survival even further. The researchers estimate that it will take at least 6 more years to confirm the survival benefit.

(Wikimedia Commons)

(Wikimedia Commons)

The numbers are small, the time elapsed short. But an extension of 1.6 years for someone with an average life expectancy of 14 years is impressive.

I very rarely use the word breakthrough. But I’ll make an exception for the continuing success story of slowing down the runaway aging clock that is progeria.

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