Highlights of the 2007 Progeria Research Foundation scientific workshop: progress in translational science.
Highlights of the 2007 Progeria Research Foundation scientific workshop: progress in translational science.
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2007 年早衰症研究基金会科学研讨会的亮点：转化科学的进展。
DOI：
10.1093/gerona/63.8.777
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发表时间：
2008
期刊：
影响因子：
--
通讯作者：
Rothman,FrankG
中科院分区：
文献类型：
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作者：
Gordon,LeslieB;Harling-Berg,ChristineJ;Rothman,FrankG
2007年春天，波士顿儿童医院开始了一项为期2年的临床药物试验（1），目的是提高Hutchinson-Gilford早衰综合征（以下简称早衰症）儿童的生活质量，这是一种罕见的（400万分之一的频率），多系统，不可避免的致命疾病，由于心肌梗死和中风，7至20岁之间的年轻人会失去生命（2）。早衰症研究基金会（PRF）组织的一系列合作科学研讨会促进了早衰症首次临床试验的进程，并得到了对衰老、心血管疾病、罕见疾病研究和遗传学感兴趣的机构的支持（http：//www.progeria.com）。早老症研究。org/2007_prf_workshop_on_progeria。html）。这些会议提供了一个集中的论坛，以促进临床医生和科学家对早衰症的集体思考，在这个鲜为人知的领域建立合作，并加速发现新的方法，推动该领域朝着治疗和治愈的方向发展。2001年的第一次PRF科学研讨会帮助鉴定了核起泡作为早衰症细胞的重要表型标记（由澳大利亚悉尼大学的Anthony韦斯指出），并识别了从早衰症患者培养的细胞中1号染色体上的易位（W.纽约州立发育障碍基础研究所的特德·布朗），他向遗传学家指出了早衰症基因突变的方向（3）。2003年，第二次研讨会在早老症基因缺陷发表后仅3个月举行，早老症是一种典型的由C！编码核纤层蛋白A的LMNA基因的核苷酸1824处的T突变（4，5）。重要的是，这种突变导致了一种异常形式的法尼基化前核层蛋白A分子（4）的持续存在，这种分子现在被称为早老蛋白。与会者现在包括核纤层蛋白生物学和核纤层蛋白病领域的专家。2004年在国家人类基因组研究所（NHGRI）举办的早衰症研讨会专门讨论了干细胞的作用和干细胞移植在早衰症中的潜力，这是该领域持续关注的一个领域。在2005年的一般性早衰症研讨会上，两种早衰症的小鼠模型被公布，尽管它们含有相同的突变，但它们产生了非常不同的表型，模拟了人类疾病的各个部分（6，7）。关于法尼基转移酶抑制剂（FTIs）在治疗早衰症中的潜在作用的早期体外数据由四个实验室提出，证明FTI可以逆转表达早老蛋白的细胞中的核起泡（8-11）。有数据表明，用FTI治疗新开发的细胞测定可改善或逆转早老蛋白积累的一些影响，2007年5月开始了一项用FTI治疗早衰症儿童的临床试验（1）（www. ClinicalTrials. gov）。
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).