《新英格兰医学杂志》5月15日报道，美国费城儿童医院Kiran Musunuru、Ahrens-Nicklas博士等专家及其团队，利用碱基编辑技术，为一名罕见尿素循环障碍——氨甲酰磷酸合成酶1（CPS1）缺乏症的新生儿定制体内基因疗法，成功缓解病情。这是全球首次针对“单患者独特突变”（N-of-1 variants）的体内基因编辑治疗，为超罕见病精准医疗开辟新路径。
（一）病情凶险：超罕见代谢病危及生命
CPS1缺乏症是一种超罕见常染色体隐性遗传病，发病率约1/130万，患儿因肝脏线粒体酶功能缺失，无法正常代谢血氨，出生后常迅速出现危及生命的高氨血症。本例患儿出生48小时内即出现嗜睡、呼吸窘迫，血氨升高超过1000μmol/L（正常值9-33μmol/L），需持续肾脏替代治疗，5个月时已列入肝移植名单。
（二）精准定制：6个月“量身打造”基因疗法
患儿携带两个CPS1截断突变，Q335X（父系）和E714X（母系）。研究者在CPS1 Q335X变异细胞基础上开发了基于CRISPR-Cas9的腺嘌呤碱基编辑器（ABE），以脂质纳米颗粒（LNP）递送，疗法简称为“k-abe”。关键流程如下：
1.突变建模与编辑器筛选：通过细胞和小鼠模型，筛选出高效精准的NGC-ABE8e-V106W碱基编辑器及向导RNA（gRNA），可将致病位点的腺嘌呤（A）精准编辑为鸟嘌呤（G），恢复CPS1酶功能。
2.跨物种安全性验证：食蟹猴毒理实验显示，0.1mg/kg的剂量对患者来说是潜在安全的初始临床剂量，并且可观察到肝脏校正编辑效应。
3.紧急审批与个体化治疗：通过 FDA“单患者扩展访问”机制紧急审批，患儿在7个月和8个月时分别接受0.1mg/kg（首次）和0.3mg/kg（第二次）静脉输注，同时采用西罗莫司+他克莫司进行免疫抑制治疗。
（三）治疗成效：代谢改善与病毒感染耐受双重突破
1.核心生化指标优化：
蛋白质摄入量显著增加，氮清除药物的使用剂量减半，血氨水平稳定在正常范围（中位数从治疗前23μmol/L降至13μmol/L），尿乳清酸水平从正常下限升至正常或偏高范围，反映CPS1酶功能恢复。
2.临床耐受性提升：
治疗后患儿经历轮状病毒胃肠炎、鼻病毒感染等多次挑战，均未出现高氨血症危象，且无需中断正常饮食。体重从第9百分位（7.14kg）升至第26百分位（8.17kg），神经系统发育保持稳定。
（四）技术突破：开启“一人一药”基因治疗新时代
传统基因疗法受限于“常见突变”和病毒载体免疫原性，而 K-abe通过模块化设计（通用LNP载体+个性化gRNA），实现了从基因突变鉴定到疗法上市仅6个月的快速响应。这种“量身定制”模式无需依赖供体器官，且规避了腺相关病毒（AAV）疗法的单次给药限制，为数百种肝脏代谢遗传病（如酪氨酸血症、枫糖尿病）提供了可复制的治疗范式。
（五）研究局限与未来方向
尽管短期数据显示安全性和有效性，研究团队强调需长期随访（目前仅7周）以评估编辑效果的持久性及潜在脱靶效应。由于未进行肝活检，尚无法直接验证肝细胞编辑效率；尽管同类LNP疗法在动物实验中未检测到生殖细胞编辑，但该风险仍需持续监测。
这项研究不仅为超罕见病患者带来生存希望，更标志着基因编辑技术从“通用型”向“精准化”的关键跨越，为“一人一药”的个性化医疗时代奠定了重要基础。
参考文献：
1.Tjnek M, Chyliushi K, Porfira I, Hauer M, Doublard A, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science 2012;378:1624.
2.Frangasi H, Locatelli F, Sharma A, et al. Exagamglogene autotemcel for severe sickle cell disease. N Engl J Med 2024;390-1649:62.
3.Locatelli F, Lang P, Wall D, et al. Exagamglogene autotemcel for transfusion-dependent β-thalassemia. N Engl J Med 2024;390:1663-76.
4.Colin DM, Gurugama P, Magri M, et al. CRISPR-based therapy for hereditary oligodemia. N Engl J Med 2025;392:458-67.
5.Komor AC, Kim YB, Becker MS, Zuris JA, Liu DG. Programmable editing of a target base in genomic DNA without double-stranded DNA cleavage. Nature 2006;538:420-4.
6.Gandolfi NM, Kumar JC, Rees HA, et al. Programmable base editing of A•T to G•C in genomic DNA without DNA cleavage. Nature 2017;551:464-71.
7.Anzalone AW, Randolph PB, Davis JR, et al. Search-and-replace genome editing without double-strand breaks or donor DNA. Nature 2019;576:149-57.
8.Ngueragung Wakap S, Lambert DM, Olty A, et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur J Hum Genet 2020;28:165-73.
9.Umov PD. Give Cas a chance: an actionable path to a platform for CRISPR cures. CRISPR J 2024;721:9.
10.Summar ML, Koelker S, Predenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab 2013;110:179-80.
11.Nettesheim S, Kolker S, Karall D, et al. Incidence, disease onset and short-term outcome in urea cycle disorders - cross-border surveillance in Germany, Austria and Switzerland. Orphanet J Rare Dis 2017;12:111.
12.Bates TR, Lewis BD, Burnett JR, et al. Late-onset carbamyl phosphate synthetase 1 deficiency in an adult cured by liver transplantation. Liver Transpl 2011;17:1481-4.
13.Pritchard AB, Izumi K, Payan-Walters I, Yudloff M, Rand EB, Singh E, et al. Outcomes of urea cycle disorder patients after liver transplantation: 35 patients over 27 years in one pediatric tertiary hospital. Am J Med Genet A 2022;188:1443-7.
14.Ah Mow N, Krivsky L, McCarten R, Batkner M, Technan M, Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr 2013;160(2):334-9.e1.
15.Choi Y, Oh A, Lee Y, et al. Unfavourable clinical outcomes in patients with carbamoyl phosphate synthetase 1 deficiency. Clin Chim Acta 2022;58:65-61.
16.Rose NE, Garback SE, Gleich E, et al. Severity-adjusted evaluation of liver transplantation on health outcomes in urea cycle disorders. Care Med 2024;26(6):10109.
17.Kido J, Matsumoto S, Sugawara K, Sawada T, Nakamura K. Variants associated with urea cycle disorders in Japanese patients: nationwide data and literature review. Am J Med Genet A 2021;185:2036.
18.Musumur R, Chashvick AG, Miroguchi T, et al. In vivo CRISPR base editing of PCSK9 durably lowers cholesterol in primates. Nature 2021;593:429-34.
19.Leedo, Maszola AM, Braun MC, et al. Efficacy and safety of a single-course CRISPR base-editing therapy targeting PCSK9 in nonhuman primate and mouse models. Circulation 2023;147:2425.
20.Lazzarotto CR, Malinin NL, Li Y, et al. CHANGE-seq reveals genetic and epigenetic effects on CRISPR-Cas9 genome-wide activity. Nat Biotechnol 2020;381:317-27.
21.Tsai XQ, Zheng X, Nguyen MT, et al. GUIDE-seq reveals genome-wide profiling of off-target cleavage by CRISPR-Cas nucleases. Nat Biotechnol 2015;33:187-97.
22.Song L, Nguyen V, Xie L, et al. ATPase copper transporting beta (ATP7B) is a novel target for improving the therapeutic efficacy of docetaxel by disulfiram/copper in human prostate cancer. Mol Cancer Ther 2024;23:845-63.
23.Koeberl D, Schulze A, Sondheimer N, et al. Interim analyses of a first-in-human phase 1/2 mRNA trial for propionic acidemia. Nature 2019;628:8727.
24.Kim J, Hu C, Moulawat El Achkar C, et al. Patient-customized oligonucleotide therapy for a rare genetic disease. N Engl J Med 2019;369:244-52.
25.Kim J, Woo S, de Gusmao CM, et al. A framework for individualized splice-switching oligonucleotide therapy. Nature 2023;619:283-36.
责编：煎薯片
审核：张影
