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Lonafarnib Slows ‘Untreatable’ Progeria Syndrome

Findings have implications for aging in general (Sept. 25)

The American Society for Cell Biology (ASCB) reported on September 25 that positive results have been achieved in a clinical drug trial at Boston Children’s Hospital for the previously “untreatable” rapid-aging disorder in children known as progeria.

A baby born with progeria will stop growing by 16 to 18 months and will quickly develop signs of old age, including hair loss, thin skin, osteoporosis, and, most dangerously, progressive arteriosclerosis. By 10 years of age, children with progeria appear to be 80.

The new clinical trial grew out of the identification of the defective progeria gene, LMNA, in 2003. Later cell-biology research found a link between progeria and defective proteins (lamins) that make up the envelope surrounding the cell nucleus. Further research revealed that a greasy tag molecule, farnesyl, accumulates on defective lamin A proteins, eventually warping the structure of the nuclear envelope and disrupting the orderly production of genetic messages in the nucleus that direct normal growth.

The identification of the defective LMNA gene transformed progeria into a “laminopathy” — a growing class of diseases caused by problems with nuclear lamins. Normal aging is thought to involve many of the same processes as laminopathies and gives the new clinical trial implications beyond progeria.

With the discovery of the lamin link, clinical researchers began looking for farnesyl transferase inhibitors (FTIs) for the treatment of progeria. They focused on lonafarnib, an FTI drug developed by Merck that was found to be safe for use in children but was ineffective against its brain-cancer targets.

In the new clinical trial, physicians at Boston Children’s Hospital observed a significant slowing of bone loss and blood-vessel blockage after administering lonafarnib to 26 children with progeria for 2½ years.

The study was published in the Proceedings of the National Academy of Sciences.

For more information, visit the ASCB Web site.

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