Something big is going on right now in the world of research.

Something very specific for some very special children with a very rare disease. It may not be widely known by name but I am sure you have seen these children. The disease is called Progeria. From the Progeria Research Foundation’s website, we learn:

Hutchinson-Gilford Progeria Syndrome “Progeria” or “HGPS” is a rare, fatal genetic condition characterized by an appearance of accelerated aging in children*. Its name is derived from Greek and means “prematurely old.” While there are different forms of Progeria, the classic type is Hutchinson-Gilford Progeria Syndrome, which was named after the doctors who first described it in England: in 1886 by Dr. Jonathan Hutchinson, and in 1897 by Dr. Hastings Gilford. Progeria affects approximately 1 in 4 – 8 million newborns. There are an estimated 200-250 children living with Progeria worldwide at any one time. It affects both sexes equally and all races. Since The Progeria Research Foundation was created in 1999, we have discovered children with Progeria living in over 40 countries.”

Most of us will have come across a picture of one of these children in the papers, on TV, or on the internet. We remember them because they look different from other kids their age. If you ever get the privilege to chat with them, you will find that are some of the wisest people you will ever meet. To speak with them is truly inspiring because of their personalities and outlook on life. It is also heart wrenching because we know most will never reach their twenties.

About eight years ago I was working as a veterinary technician in a research facility. During that time a new investigator moved his lab into our facility, and we received his colony of mice a few weeks before he arrived. After we had cared for the mice for a few days, we started to see some very strange things. The weanlings were sometimes very small, and occasionally they were also thin. It was strange to see mice that were so young but looked like such old men. The reason was simple, these mice had been genetically modified to carry the same defective Lamin A gene that is responsible for Hutchinson-Gilford progeria syndrome in children. The ‘sick’ mice we saw were actually mice with Progeria!”

Several years later Dr. Stephen G. Young and colleagues at UCLA published a study that detailed what they found within this small population of mice (1). Once a GM model of mice had been developed, cells from these mice were studied (2). When a farnesyltransferase inhibitor was used in vitro on these cells, it showed this drug was a possible treatment for this terrible disease. Once this was learned, they went on to the next step which was to test farnesyltransferase inhibitor in vitro on cells from actual Progeria patients (3). When these studies looked very promising, confirming that the process occurring in the mouse and human cells were very similar, the GM mice were once again indispensable for the first in vivo study to determine if farnesyltransferase inhibitors could improve the health of mice with Progeria (1). This is the part that cannot be replicated by any calculations, test tube chemicals or computer programs. Without in vivo studies, it is impossible to know what a treatment will do in a living creature. The mice that were born with Progeria were given a farnesyltransferase inhibitor. Would they get better or would they stay the same? Once the study was complete, all results were compared and this therapy looked very promising indeed!

Professor Young gave a talk on his progeria research to the Congressional Medical Research Caucus in 2009, in which he discusses his group’s GM mouse studies in much more detail, and you can watch the video here.

From there, a drug needed to be developed that could be evaluated in children with Progeria. This is a process that can often take many years, but fortunately some farnesyltransferase inhibitors designed as cancer treatments looked promising (see more about it here). lonafarnib was selected for clinical trials in progeria because it had already been assessed in pediatric cancer clinical trials where it had a demonstrated an acceptable safety profile. This is how decades of drug development happened in less than 10 years.

Researchers were able to move many steps ahead, much closer to the Progeria clinical trials that were needed. Remember, the one thing these children do not have is time. They grow old and die, sometimes as young as seven, and very rarely live past twenty. Most die in their teens. If a completely new drug had been needed, nearly every child alive with the disease that day would have passed away by the time it was ready for a clinical trial.

I think it is very important to explain briefly genetic disease and the role GM play in finding treatments and cures. Francis Collins is a well known and oft cited geneticist and physician, and currently Director of the National Institutes of Health, who gave a TED talk in April 2012 about this very topic. Dr. Collins has long been interested in Progeria, he led the team that first identified defects in the Lamin A gene as a cause of Hutchinson-Gilford progeria syndrome in 2003, and later in 2008 published a study that examine the effect of farnesyltransferase inhibitors on cardiac defects in a mouse model of Progeria (cardiac defects are the most common cause of death in children with Progeria).



At the most basic, a genetic disease is caused when there is a faulty gene somewhere in the genetic code. While the *reason* the gene is broken may be a mystery, there are roughly 4,000 genetic diseases that scientists at least know what gene is causing the problem, which is the case for Progeria. Scientists know what is causing the problem, but how do you fix it? Dr. Collins has a vision of accelerating the transition from the bench to the bedside, and the example of progeria shows that one of best tools for finding the treatments and cures is Genetically Modified mice. Our GM mice.

In the case with Progeria, researchers were able to create the same disease in mice that was found in humans, effectively mirroring the disease. By doing this, they are able to study not just the disease itself, but study treatments on a live organism with the disease. With GM mice, researchers are able to find treatments and cures at an unprecedented pace. As Dr. Mark Kieran, who led the first clinical trial of lonafarnib to treat progeria (4), said:

PRF (Progeria Research Foundation)provides a model for disease research organizations, and is a good example of successful translational research, moving from gene discovery to clinical treatment at an unprecedented pace,”

There are over 4,000 genetic diseases known to us right now, yet only 250 of them have treatments. If we can find help for these people so quickly, why are there so few cures? One reason is that in many cases there are still no mouse model available to study. In our case of Progeria, a mouse model of the disease was developed which sped up research by years or even decades. Without GM mice, this treatment would not be available now. Progeria clinical trials moved very quickly compared to most treatments and it was announced in September of 2012. Finally, these children had a treatment! While this is not a cure, it is a huge step forward. With early diagnosis and treatment, these children have a much better chance at a normal life!

Because of the extremely rare occurrence of this disease, these children can be hard to find, especially in less developed countries where they may have never seen this disease before. In 2009, the Progeria Research Foundation (PRF)launched the “Find the Other 150” campaign. As of September 2012, they were aware of 96 of the estimated 200-250 children living with Progeria. If you are aware of any of these children, please visit www.FindTheOther150.org to find information on how to participate in future studies.

I have spent nearly a decade in this field now. I will always remember those mice and those children. To see a treatment developed and to even have played a small part it helping it happen is humbling. Will I make headlines? No. Will my name ever be in a published paper? Probably not. Will I make millions off any of the discoveries I participate it? Never. I went into this field knowing full well I will never get rich or retire early and wealthy. That is not why I am here. I choose to do what I do because of people out there like these Progeria kids. I do this for them, and all the millions of cancer patients out there like my late husband. I do this so we can find a cure.

And to know I had even a tiny part in making that cure happen, that, is priceless.

Pamela Bass

1) Yang SH, Meta M, Qiao X, Frost D, Bauch J, Coffinier C, Majumdar S, Bergo MO, Young SG, Fong LG.”A farnesyltransferase inhibitor improves disease phenotypes in mice with a Hutchinson-Gilford progeria syndrome mutation.” J Clin Invest. 2006 Aug;116(8):2115-21

2) Yang SH, Bergo MO, Toth JI, Qiao X, Hu Y, Sandoval S, Meta M, Bendale P, Gelb MH, Young SG, Fong LG.”Blocking protein farnesyltransferase improves nuclear blebbing in mouse fibroblasts with a targeted Hutchinson-Gilford progeria syndrome mutation.” Proc Natl Acad Sci U S A. 2005 Jul 19;102(29):10291-6. Epub 2005 Jul 12.

3) Toth JI, Yang SH, Qiao X, Beigneux AP, Gelb MH, Moulson CL, Miner JH, Young SG, Fong LG. “Blocking protein farnesyltransferase improves nuclear shape in fibroblasts from humans with progeroid syndromes.” Proc Natl Acad Sci U S A. 2005 Sep 6;102(36):12873-8. Epub 2005 Aug 29.

4) Gordon LB, Kleinman ME, Miller DT, Neuberg DS, Giobbie-Hurder A, Gerhard-Herman M, Smoot LB, Gordon CM, Cleveland R, Snyder BD, Fligor B, Bishop WR, Statkevich P, Regen A, Sonis A, Riley S, Ploski C, Correia A, Quinn N, Ullrich NJ, Nazarian A, Liang MG, Huh SY, Schwartzman A, Kieran MW. “Clinical trial of a farnesyltransferase inhibitor in children with Hutchinson-Gilford progeria syndrome.” Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666-71. doi: 10.1073/pnas.1202529109. Epub 2012 Sep 24.