Kotit Susy
Aswan Heart Centre (AHC), Aswan, Egypt.
Glob Cardiol Sci Pract. 2023 Jan 30;2023(1):e202304. doi: 10.21542/gcsp.2023.4.
Transthyretin amyloidosis (ATTR amyloidosis) is a progressive fatal disease characterized by accumulation of amyloid fibrils composed of misfolded transthyretin (TTR) protein in tissues, resulting in cardiomyopathy and heart failure. Approximately 50,000 people have hereditary ATTR amyloidosis, and up to 500,000 have wild-type ATTR amyloidosis globally, leading to poor quality of life and high morbidity, resulting in death within a median of 2 to 6 years after diagnosis. However, data on the prevalence of ATTR-CM is limited and poorly characterized. NTLA-2001, an in vivo gene-editing therapeutic agent designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum by knocking out the TTR gene, has been shown to be effective, presenting a new therapeutic strategy. However, the safety, tolerability, and pharmacodynamic response to IV NTLA-2001 administration has not been yet demonstrated. The first-in-human in vivo CRISPR/Cas9 trial of TTR Gene editing by NTLA-2001 in patients with Transthyretin Amyloidosis and cardiomyopathy was designed to evaluate the safety, tolerability, efficacy, and pharmacokinetic and pharmacodynamic responses to IV NTLA-2001 administration and its effect on serum transthyretin (TTR) levels in patients with ATTR amyloidosis and cardiomyopathy. Twelve subjects received NTLA-2001 (three NYHA I/II subjects at 0.7 mg/kg, three subjects at 1.0 mg/kg, and six NYHA III subjects at 0.7 mg/kg). Serum TTR levels were reduced from the baseline in all subjects (mean>90% after 28 days). Mean % reductions (+/-SEM) from baseline to day 28 were: NYHA I/II at 0.7 mg/kg = 92% (1%), at 1.0 mg/kg = 92% (2%), and for NYHA III at 0.7 mg/kg = 94% (1%) maintained through 4-6 months. Two of the 12 patients (16.7%) reported a transient infusion reaction. One patient experienced a grade 3 infusion-related reaction that resolved without any clinical sequelae. This study showed a significant and consistent reduction in serum TTR protein levels after a single admission, while being generally well tolerated, representing a potential new option for the treatment and improvement of the prognosis of cardiac ATTR amyloidosis. Further research into the long-term safety and efficacy of NTLA-2001, particularly in higher-risk patients, including continued monitoring of whether knockout of the TTR gene results in sustained TTR reduction over the long term, is essential. Evaluation of the potential effects of markedly reduced TTR levels on patients' clinical outcomes, with a focus on functional capacity, quality of life, and mortality benefits are essential. The analysis of the use of this technology for an array of other diseases is vital.
转甲状腺素蛋白淀粉样变性（ATTR淀粉样变性）是一种进行性致命疾病，其特征是由错误折叠的转甲状腺素蛋白（TTR）组成的淀粉样纤维在组织中积聚，导致心肌病和心力衰竭。全球约有5万人患有遗传性ATTR淀粉样变性，多达50万人患有野生型ATTR淀粉样变性，导致生活质量低下和高发病率，诊断后中位2至6年内死亡。然而，关于ATTR-CM患病率的数据有限且特征描述不佳。NTLA-2001是一种体内基因编辑治疗药物，旨在通过敲除TTR基因降低血清中TTR的浓度来治疗ATTR淀粉样变性，已被证明是有效的，提出了一种新的治疗策略。然而，静脉注射NTLA-2001的安全性、耐受性和药效学反应尚未得到证实。NTLA-2001在转甲状腺素蛋白淀粉样变性和心肌病患者中进行的首次人体CRISPR/Cas9体内TTR基因编辑试验旨在评估静脉注射NTLA-2001的安全性、耐受性、疗效、药代动力学和药效学反应，以及其对ATTR淀粉样变性和心肌病患者血清转甲状腺素蛋白（TTR）水平的影响。12名受试者接受了NTLA-2001（3名纽约心脏协会I/II级受试者接受0.7mg/kg，3名受试者接受1.0mg/kg，6名纽约心脏协会III级受试者接受0.7mg/kg）。所有受试者的血清TTR水平均从基线下降（28天后平均下降>90%）。从基线到第28天的平均下降百分比（+/-SEM）为：纽约心脏协会I/II级0.7mg/kg=92%（1%），1.0mg/kg=92%（2%），纽约心脏协会III级0.7mg/kg=94%（1%），持续4至6个月。12名患者中有2名（16.7%）报告了短暂的输液反应。1名患者经历了3级输液相关反应，反应消退后无任何临床后遗症。这项研究表明，单次给药后血清TTR蛋白水平显著且持续降低，同时总体耐受性良好，代表了治疗心脏ATTR淀粉样变性和改善预后的潜在新选择。进一步研究NTLA-2001的长期安全性和有效性，特别是在高危患者中，包括持续监测TTR基因敲除是否能长期持续降低TTR，至关重要。评估TTR水平显著降低对患者临床结局的潜在影响，重点关注功能能力、生活质量和死亡率益处，至关重要。分析该技术在一系列其他疾病中的应用也至关重要。
