This web page was created as an assignment for Genetics 677, an undergraduate course at UW-Madison.
The Future of Progeria Studies
Ongoing Research
The speed at which clinical drug trials to treat HGPS were reach was unprecedented. In only five years, from the time the cause of HGPS was discovered, clinical trials began. By the end of 2009 stage II of these trials will be completed and the results will be published thereafter. The drug being used is a farnesyl transferase inhibitor, FTI. This inhibitor disrupts farneslyation of lamin A and does not allow it to associate with the nuclear membrane of the cell, therefore avoiding blebbing. These FTIs were discovered to rescue the progeria phenotype in mice and since has been brought into drug trials for children. Though, this has been a very large step in research on HGPS it is far from promising. FTIs may rescue the phenotype of the cell, as far as how it appears, it does not correct for the dysfunctional lamin. Think of it like this, why would the cell farnesylate the lamin A allowing it to associate with the nuclear membrane, then cleave of the farnesylated end allowing the lamin to go back to the inner portion of the nucleus if it was not needed?
There is some sort of value with the membrane association of lamin A, however, FTIs prevent this association. It seems that this drug may have little use at all treating HGPS patients. However, it is now being implicated in AIDS research. The video below goes into detail about FTIs and their use in AIDS and HGPS treatment. On a grimmer note, Dr. Robert Goldman of Northwestern University, a lead researcher on intermediate filaments, felt that this disease was to progressive to really treat, noting that onset occurs very early in life due to de novo mutations, making it unlikely to screen for since it is so rare, and progresses so rapidly that it would be nearly impossible to cure or treat this disease with any sort of efficacy. Steps like these taken due offer hope to those touched by progeria, illustrating the swiftness of science to identify the root of diseases and find ways to combat them. (1)
Ideas for Future Research
Throughout the semester, I have scanned database after database and looked at numerous research papers discussing the role of LMNA in HGPS. From this, I got a very good idea of what has been researched, the direction these studies are going, and possible avenues to look into more carefully.
1. First, microarray analysis of tissue culture from an HGPS patient would be very useful. Looking at this would provide a expression library of all the genes being overexpressed and repressed. This would give a better scope of what is occurring on a molecular level in a cell expressing HGPS symptoms.
2. Second, 2D SDS-PAGE analyses would be very useful. The problem with this type of test is that it takes a time-dependent snapshot of the proteins in a cell. After different times; day or night, times of stress, etc., this snapshot changes dramatically. However, the mutation causing HGPS is very well characterized and the time during the cell cycle it occurs is well known. This would allow researchers to better target the interacting proteins of lamin A and research their role in this disease.
3. LMNA's function is vital to the cell and cannot be aggressively targeted by drugs without causing some sort of other cellular dysfunction. Therefore, more research needs to be done on the interacting proteins with lamin A. ZMPSTE24, an enzyme responsible for lamin A cleavage, would be a good candidate for this intial research. Possibly manipulating this would allow for proper cleavage of lamin A without disrupting other cellular functions.
The difficulty in treating HGPS is that it is a de novo mutation that inherently causes a 50 amino acid deletion that contains a vital recognition site for other cellular components. This cannot be replaced, so some sort of novel solution must be found to compensate for this loss and restore the function of that lost region. Given how quickly research has progressed with this disease, HGPS patients and their family should remain hopeful.
References
1. B. C. Capell et al., Inhibiting farnesylation of progerin prevents the characteristic nuclear blebbing of Hutchinson-Gilford progeria syndrome. Proc. Natl. Acad. Sci. U.S.A.., 29 August 2005 [e-pub ahead of print]. doi:10.1073/pnas.0506001102
Peter St. Andre [email protected] Last updated:2/3/09
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