Treatment for 'Untreatable' Progeria has Roots in Basic Cell Research
Clinical trial reports significant slowing of rare rapid aging disorder, progeria, in children
The good news being widely reported, is of positive results from a clinical drug trial at Boston Children's Hospital. The previously "untreatable" rapid aging disorder in children known as progeria is rooted in basic biology discoveries made in recent years.
In the two and a half year since the clinical trial began, physicians at Boston Children's have given Lonafarnib to 26 children with progeria.
The use of farnesyl transferase inhibitors (FTI)
significantly slows the progress of progeria,
a rare and until now "untreatable"
lethal genetic disorder.
Known as Hutchinson-Gilford Progeria Syndrome
(HGPS), progeria has been described as out-of-control
rapid aging in children. A ""normal"" baby born
with HGPS will stop growing by 16-18 months
and quickly develop signs of old age including
hair loss, thin skin, osteoporosis and, progressive
arteriosclerosis. By 10 years of age
progeria children appear to be 80.
The work published in the Proceedings of the National Academy of Sciences (PNAS) paper shows a significant slowing of bone loss and blood vessel blockage in children with progeria. The clinical trial grew out of the identification of the defective progeria gene, LMNA, in 2003 by the Human Genome Project and the laboratory of current NIH Director, Francis Collins.
But the link to defective proteins called lamins that make up the envelope surrounding the cell nucleus came about through "untargeted" basic cell biology research.
Veteran lamin researchers remember having
their grant applications dismissed by
review panels as "boring" and irrelevant.
But basic work by Robert Goldman of
Northwestern University School of Medicine
and other nuclear lamin researchers around the world
revealed that a greasy tag molecule called farnesyl
accumulates on defective Lamin A proteins.
The Lamin A protein burdened with farnesyl molecules,
eventually warps the structure of the entire nuclear
envelope, disrupting the orderly dispersion of gene
messages to direct normal growth within the nucleus.
The identification of the defective LMNA gene transformed progeria into a "laminopathy," a now growing class of diseases caused by problems with the once-irrelevant nuclear lamins. "Normal" aging is thought to involve many of the same processes as do laminopathies.
With the discovery of the lamin link, clinical researchers were suddenly looking for farnesyl transferase inhibitors (FTI) to treat progeria. They zeroed in on Lonafarnib, an FTI drug developed by Merck. It had been extensively tested and found safe for use in adults and children, but ineffective against its initial brain cancer targets.
The American Society for Cell Biology has been reporting on progeria since 2006. In 2008, the ASCB Newsletter published a report on the proposed clinical drug trial. The ASCB has pulled together a file of these earlier reports for reporters and the general public interested in the deeper scientific background of progeria at: http://www.ascb.org/progeria-background.html
The PNAS paper was published online before print September 24, 2012, doi: 10.1073/pnas.1202529109 PNAS September 24, 2012 Gordon, Leslie B. et al, Clinical trial of a farnesyltransferase inhibitor in children with HutchinsonGilford progeria syndrome
Reporters: For further information, contact ASCB Science Writer John Fleischman, email@example.com or 513-706-0212.
Original article: http://www.ascb.org/index.php?option=com_content&view