Highlights of the 2007 Progeria Research Foundation Scientific Workshop: Progress in Translational Science

Extract

1Warren Alpert Medical School of Brown University, 2Brown University, Providence, Rhode Island.

IN the spring of 2007, a 2-year clinical drug trial began at Children's Hospital Boston (1) with the goal to advance the quality of life for children with Hutchinson-Gilford progeria syndrome (henceforth progeria), a rare (frequency 1 in 4 million), multisystem, and inevitably fatal disease that claims young lives due to myocardial infarctions and strokes between ages 7 and 20 years (2). The journey to the first clinical trial for progeria has been facilitated by a series of collaborative scientific workshops organized by The Progeria Research Foundation (PRF) and supported by agencies interested in aging, cardiovascular disease, rare disease research, and genetics (http://www.progeriaresearch.org/2007_prf_workshop_on_progeria.html). These meetings have provided a concentrated forum to facilitate the collective thinking of clinicians and scientists about progeria, forge collaborations in this little-known field, and accelerate the discovery of new ways to push the field forward toward treatments and cure. The first PRF Scientific Workshop in 2001 helped to identify nuclear blebbing as an important phenotypic marker of progeria cells (noted by Anthony Weiss; University of Sydney, Australia), and to recognize a translocation on chromosome 1 in the cells cultured from a progeria patient (W. Ted Brown, New York State Institute for Basic Research in Developmental Disabilities), pointing geneticists in the direction of the gene mutation for progeria (3). In 2003, the second workshop was held just 3 months after publication of the gene defect in progeria, which is typically a sporadic autosomal dominant disease caused by a C → T mutation at nucleotide 1824 of the LMNA gene encoding lamin A (4,5). Importantly, the mutation results in a persistence of an aberrant form of a farnesylated-prelamin A molecule (4) now called progerin. The attendees now included experts in the field of lamin biology and laminopathies. The 2004 Progeria Workshop, held within the National Human Genome Research Institute (NHGRI), was held specifically to discuss the role of stem cells and the potential for stem cell transplantation in progeria, an area of continuing interest for the field. At the general Progeria Workshop in 2005, two mouse models of progeria were unveiled and, although they contained identical mutations, they yielded very different phenotypes, mimicking various portions of the human disease (6,7). Early in vitro data on a potential role of farnesyltransferase inhibitors (FTIs) in treating progeria were presented by four laboratories, demonstrating that FTI could reverse nuclear blebbing in cells expressing progerin (8–11). Armed with data demonstrating that treatment of newly developed cellular assays with FTIs improves or reverses some of the effects of progerin accumulation, a clinical trial treating children with progeria with an FTI was initiated in May 2007 (1) (www.clinicaltrials.gov).