Department of Anesthesia, Boston Children's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 2012 Oct 9;109(41):16666-71. doi: 10.1073/pnas.1202529109. Epub 2012 Sep 24.
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in LMNA that produces the farnesylated aberrant lamin A protein, progerin. This multisystem disorder causes failure to thrive and accelerated atherosclerosis leading to early death. Farnesyltransferase inhibitors have ameliorated disease phenotypes in preclinical studies. Twenty-five patients with HGPS received the farnesyltransferase inhibitor lonafarnib for a minimum of 2 y. Primary outcome success was predefined as a 50% increase over pretherapy in estimated annual rate of weight gain, or change from pretherapy weight loss to statistically significant on-study weight gain. Nine patients experienced a ≥50% increase, six experienced a ≥50% decrease, and 10 remained stable with respect to rate of weight gain. Secondary outcomes included decreases in arterial pulse wave velocity and carotid artery echodensity and increases in skeletal rigidity and sensorineural hearing within patient subgroups. All patients improved in one or more of these outcomes. Results from this clinical treatment trial for children with HGPS provide preliminary evidence that lonafarnib may improve vascular stiffness, bone structure, and audiological status.
亨廷顿舞蹈病-吉福德早衰综合征（HGPS）是一种极其罕见的致命性节段性过早衰老综合征，由 LMNA 突变引起，产生了法尼基化异常的 lamin A 蛋白——前质素。这种多系统疾病导致生长不良和动脉粥样硬化加速，从而导致早逝。法尼基转移酶抑制剂在临床前研究中改善了疾病表型。25 名 HGPS 患者接受法尼基转移酶抑制剂 lonafarnib 治疗至少 2 年。主要结局成功定义为治疗前体重增加率增加 50%，或从治疗前体重减轻转为统计学上显著的研究期间体重增加。9 名患者体重增加≥50%，6 名患者体重减少≥50%，10 名患者体重增加率稳定。次要结局包括患者亚组的动脉脉搏波速度和颈动脉回声密度降低，以及骨骼僵硬和感觉神经性听力增加。所有患者在这些结局中的一个或多个方面均有改善。针对 HGPS 儿童的这项临床治疗试验的结果提供了初步证据，表明 lonafarnib 可能改善血管僵硬、骨骼结构和听力状况。
