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Biological Chemistry

Progeria Drug Prospect Found

Rare Diseases: Small molecule corrects defects in cells from patients with premature-aging condition

by Stu Borman
May 2, 2014 | A version of this story appeared in Volume 92, Issue 18

Two cells, stained blue. The one on the right is a tidy ovoid with one small green circle and one green butterfly shape inside. The one on the left is chaotic in overall shape, but it’s two green shapes are both tidy circles.
Credit: Courtesy of Delphine Larrieu
Untreated cell nucleus from progeria patient (left, stained blue, with nucleoli in green) is misshapen. In remodelin-treated cell (right), nuclear shape is normal.

A small molecule called remodelin that corrects cell defects associated with the premature-aging disease progeria has been discovered. There is currently no effective treatment for progeria, and the discovery could help lead to one. But the compound has not yet been tested in animals, so its promise has yet to be confirmed.

Progeria, also called Hutchinson-Gilford progeria syndrome, is a genetic disorder that causes children to appear prematurely aged and develop conditions such as baldness, osteoporosis, atherosclerosis, and cardiovascular disease. Estimated to affect about one newborn of every 4 million worldwide, it is often fatal by early teenage years.

Researchers have now identified remodelin as a possible treatment and have nailed down its mechanism. The work was carried out by Delphine Larrieu, Sébastien Britton, Mukerrem Demir, and Stephen P. Jackson at Cambridge University’s Gurdon Institute and Raphaël Rodriguez at France’s CNRS Institute for Natural Substances Chemistry (Science 2014, DOI: 10.1126/science.1252651).

In cells of patients with progeria and related conditions known as laminopathies, mutations in the gene for lamin A protein cause misshapen cell nuclei and DNA damage. The researchers screened compound libraries for an agent that might normalize misshapen nuclei and reduce DNA damage in laminopathic cells. That effort yielded remodelin.

The team then used click chemistry, liquid chromatography/mass spectrometry, fluorescence microscopy, circular dichroism spectroscopy, and other techniques to reveal that remodelin works by inhibiting an acetyltransferase called NAT10. NAT10 inhibition restores normal cell-nucleus shape and reduces DNA damage, in part by modifying cell architectural elements called microtubules.

Previous work had shown that certain farnesyltransferase inhibitors could also improve nuclear shape in progeria cells. But in clinical trials they improved progeria symptoms only modestly, and the design of those trials has led some to question their validity. The researchers think remodelin might have a better chance because it not only restores nuclear shape but also reduces DNA damage.

Progeria expert Nicolas Lévy of Aix-Marseille University, in France, comments that although remodelin has been shown to correct nuclear shape and DNA structure, a successful therapy will also have to correct other cellular pathway irregularities observed in progeria.

Howard J. Worman of Columbia University, a cell nucleus inherited-disease specialist, calls the findings “a great basic discovery” but says the agent “has to be taken to the next step by testing it in animal models.”

If remodelin’s efficacy extends to progeric mice, “this strategy may lead to an ultimate treatment,” adds cell biologist Ya-Hui Chi of the National Health Research Institutes, in Zhunan, Taiwan.

The research team plans to test remodelin in progeria mouse models. The researchers have filed a patent application for the agent and are now in discussions with big pharma companies to take over drug ­development.



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