What's News in Progeria Research

HGPS has previously been shown to affect many fundamental cellular functions including replication, gene expression, and DNA repair. Busch and coworkers have added the transport of proteins from the cytoplasm into the nucleus to this list. All proteins are synthesized in the cytoplasm, and those that end up being in the nucleus have to get across the nuclear membrane. The transport is accomplished through channels in the nuclear membrane called "nuclear pores". Many proteins are too large to simply diffuse through the nuclear pores, but are "ushered" through them by special proteins that have evolved for this purpose. In this article, cells that express the mutant gene responsible for HGPS were found to have reduced transport of proteins into nuclei by direct measurement.

Busch A, Kiel T, Heupel WM, Wehnert M, Huebner S., “Nuclear protein import is reduced in cells expressing nuclear envelopathy-causing lamin A mutants.” Exp Cell Res. 2009 May 11.

This article is a very thoughtful and up-to-date review which will be of interest to investigators working on progeroid diseases (with emphasis on HGPS) and their relation to normal aging, It also touches on the relation of aging to cancer. Topics covered are:

     → Providing structure and organization: nuclear architecture and genome integrity
     → DNA damage and repair gone awry 
     → Old and beyond repair tumor suppressors and cellular senescence, and 
     → Regeneration and renewal: stem-cell biology. Regeneration and renewal: stem-cell biology.

The article highlights the ways in which recent advances in the study of progeroid diseases is giving insight into basic cellular functions as well as aging.

Capell BS, Tlougan BE, Orlow SJ, “From the Rarest to the Most Common: Insights from Progeroid Syndromes into Skin Cancer and Aging.” Journal of Investigative Dermatology (2009 Apr 23), 1-11

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April 2009: Past PRF Research Grantees Devise new Method to Study Progerin in Cells

Previous experiments with Fibroblast cells from Progeria patients have shown that the damage caused by the mutation is initially the result of action by the altered form of Lamin A, called Progerin. But the interpretation of these experiments can be difficult in culture for varying numbers of generations. Fong et. al. have set up an experimental system in which the amount of Progerin in Wild-type cells can be increased or decreased. This method will allow investigators to sort out the direct effects of Progerin from secondary ones, thereby advancing the study of cellular mechanisms that lead to the pathophysiology of Progeria cells.

August and October 2008: Is Progeria Reversible?
Two recent publications show that FTIs and gene therapy may do just that!    

August and October 2008: Two separate studies show that Progeria is reversible in the cardiovascular system and the skin of mouse models. The experiments were significant in not treating the mice until they expressed Progeria symptoms, whereas most previous studies began treatment before Progeria was apparent. Production of progerin (the damaging protein made from the Progeria gene) was inhibited either by treatment with a farnesyl transferase inhibitor (FTI) or by turning off the gene. In both cases the mice reverted to normal or almost normal conditions. These observations provide encouraging evidence for the current clinical trial of FTIs for Progeria.

In a stunning display of progress with the FTI drug – now being used in the First-ever Progeria Clinical Drug Trial – Dr. Francis Collins’ research team at the National Institutes of Health * found that FTI’s prevented and even reversed the most devastating effect of Progeria in mice: cardiovascular disease.* "We were amazed that [the drug] worked so well," says Francis Collins, a geneticist and former director of the National Human Genome Research Institute, who was senior author for the research team that identified the Progeria gene mutation in 2003. “Not only did this drug prevent these mice from developing cardiovascular disease, it reversed damage in mice that already had disease.”

The Progeria mice develop heart disease that mirrors that of children with Progeria. The authors found that the FTI was both able to prevent the development of heart disease to some degree when mice were treating from the time they were weaned, and partially reverse established disease when mice were treated beginning at age 9 months. “One of the striking things from my perspective was the ability to reverse disease, ” Collins said, which is critical given that Progeria is generally not diagnosed at birth, but only when children begin to show symptoms, when part of the damage already has been done.

"If these drugs are found to have similar effects in children, this could mark a major breakthrough for treating this devastating disease," said NHLBI’s Dr. Nabel, who was a co-author of the study. "In addition, these findings shed light on the potential role of FTI drugs to treat other forms of coronary artery disease."

View the article in Scientific American, “New Hope for Progeria: Drug for Rare Aging Disease”, at http://www.sciam.com/article.cfm?id=new-hope-for-progeria-drug-for-rare-aging-disease and the NIH press release at http://www.nih.gov/news/health/oct2008/nhgri-06.htm

* Capell, et. al, “A farnesyltransferase inhibitor prevents both the onset and late progression of cardiovascular disease in a Progeria mouse model.” Proceedings of the National Academy of Sciences, Vol. 105, no. 41, 15902-15907 (Oct. 14, 2008)

In a second study that was published online in the Journal of Medical Genetics**, Dr. Maria Eriksson’s research team at the Karolinska Institutet in Sweden created another mouse model of Progeria with abnormalities of the skin and teeth.  The mice are genetically engineered so that the Progeria mutation can be shut off at any time. Once disease was apparent, the gene for Progeria was turned off. After 13 weeks the skin was almost indistinguishable from normal skin. This study shows that in these tissues the expression of the Progeria mutation does not cause irreversible damage and that the reversal of disease is possible, which gives promise for treatment for Progeria.

**Eriksson, et. al., “Reversible phenotype in a mouse model of Hutchinson-Gilford Progeria syndrome.” J. Med. Genet. published online 15 Aug 2008; doi:10.1136/jmg.2008.060772
To purchase this article, go to: http://jmg.bmj.com/cgi/rapidpdf/jmg.2008.060772v1

More Evidence of the Link between Progeria and

Normal Aging and Heart Disease

The articles about these exciting studies all agree that beyond Progeria, these results have the potential to benefit all patients with cardiovascular disease. Researchers have discovered that the toxic protein responsible for Progeria is actually produced at low levels in all humans, possibly accumulating as we age. Thus, by studying these rare children, Collins says, we can further our understanding of a major mechanism of human aging—and perhaps, find new ways to slow the process.