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). The present article, detailing the 2007 PRF Scientific Workshop (November 12–14, Boston), emphasizes the complexities of progerin and lamin A biology, and the need to continue to look for the most effective protocols for correcting the effects of the lamin A defect in progeria. All speakers presented preliminary data that had not been peerreviewed at the time of presentation. In the months since the workshop, some data have been published (referenced within this article), and we look forward to additional peerreviewed publications on the work presented at this meeting over the coming year. The essence of translational research was represented in the presentations, which brought forth the most important issues in progeria today—the effects of progerin and lamins and their binding partners on the functioning of cells, systems, mouse models, and humans; the connection between progeria, aging, and cardiovascular disease in the general population; careful analysis of FTI effects on progeria at all levels (summarized in Table 1); and strategies for future disease treatments and cure. In his introduction at the workshop, Francis Collins (Director, NHGRI) noted that a 4-year period between gene discovery and a clinical drug trial is ‘‘. . . an unprecedented feat for a rare genetic disease.’’ For progeria patients and their families, who have struggled to live within a void of information, the clinical trial represents ‘‘. . . a source of light coming up after a long, long night’’ and hope has replaced ‘‘. . . a sense of fear and helplessness on each passing birthday’’ (Subbarao, father of Priya, a 15year-old with progeria).
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Mar 29, 2023
Leonardo Xochicale-Santana + 4
Open Access