囊性纤维化基因治疗研究进展

doi:10.19586/j.2095-2341.2024.0083

生物技术进展 ›› 2024, Vol. 14 ›› Issue (5): 813-819.DOI: 10.19586/j.2095-2341.2024.0083

• 进展评述 • 上一篇

囊性纤维化基因治疗研究进展

王泓恺¹(), 王俞杰¹(), 赵潇涵¹, 荆钰含¹, 唐嘉毅¹, 隋宏书²()

^1.山东第一医科大学临床与基础医学院，济南 250000
^2.山东第一医科大学临床与基础医学院组织学与胚胎学系，济南 250000

收稿日期:2024-04-15 接受日期:2024-06-11 出版日期:2024-09-25 发布日期:2024-10-22
通讯作者: 隋宏书
作者简介:王泓恺 E-mail: 1170789150@qq.com
王俞杰 E-mail: 2579728429@qq.com第一联系人：（王泓恺和王俞杰为本文共同第一作者。）
基金资助:
国家自然科学基金面上项目(81670004)

Research Progress on Cystic Fibrosis Gene Therapy

Hongkai WANG¹(), Yujie WANG¹(), Xiaohan ZHAO¹, Yuhan JING¹, Jiayi TANG¹, Hongshu SUI²()

^1.College of Clinical and Basic Medicine，Shandong First Medical University，Jinan 250000，China
^2.Department of Histology and Embryology，College of Clinical and Basic Medicine，Shandong First Medical University，Jinan 250000，China

Received:2024-04-15 Accepted:2024-06-11 Online:2024-09-25 Published:2024-10-22
Contact: Hongshu SUI

摘要/Abstract

摘要：

囊性纤维化(cystic fibrosis，CF)是由囊性纤维化跨膜调节因子(cystic fibrosis transmembrane regulator，CFTR)突变引起的常染色体隐性遗传病，其引起的肺部疾病也是致死的主要病因。自1938年发现该疾病以来，CF的治疗仅限于对症治疗，2012年CFTR调节剂的出现，明显改善了患者的健康状况与生活质量，但由于存在多种CF致病相关的突变，突变特异性靶向药物并不适用于所有遗传变异，也无法纠正疾病多系统的症状。相比之下，基因疗法不受患者基因型限制，适用于所有患者并可以彻底治愈CF，但该疗法至今仍未取得期望疗效。综述简要介绍了CF的发展历史，讨论了CF基因治疗的研究进展以及存在的问题，以期能够推动CF基因治疗的发展并为治疗其他复杂疾病提供借鉴。

关键词: 囊性纤维化, 囊性纤维化跨膜传导调节因子, 基因治疗

Abstract:

Cystic fibrosis （CF） is an autosomal recessive genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator （CFTR） gene， and CF-related lung disease is the main factors of mortality. Since its discovery in 1938， treatment for CF has been limited to symptomatic treatments， and the emergence of CFTR modulators in 2012 has substantially improved health and quality of life for patients. However， due to the presence of multiple CF-causing mutations， mutation-specific targeted therapies are not universally applicable and cannot address the multisystemic nature of the disease. In contrast， gene therapy holds promise for all patients regardless of genotype， offering the potential for complete cure， yet efficacy remains elusive. The review briefly introduced the development history of CF， discussed the research progress and existing problems of CF gene therapy， in order to promote the development of CF gene therapy and provide guidance for the treatment of other complex diseases.

Key words: cystic fibrosis, cystic fibrosis transmembrane regulator, gene therapy

中图分类号:

R450

王泓恺, 王俞杰, 赵潇涵, 荆钰含, 唐嘉毅, 隋宏书. 囊性纤维化基因治疗研究进展[J]. 生物技术进展, 2024, 14(5): 813-819.

Hongkai WANG, Yujie WANG, Xiaohan ZHAO, Yuhan JING, Jiayi TANG, Hongshu SUI. Research Progress on Cystic Fibrosis Gene Therapy[J]. Current Biotechnology, 2024, 14(5): 813-819.

参考文献 46

1	STOLTZ D A, MEYERHOLZ D K, WELSH M J. Origins of cystic fibrosis lung disease[J]. N. Engl. J. Med., 2015, 372(16): 1574-1575.
2	GRIESENBACH U, DAVIES J C, ALTON E. Cystic fibrosis gene therapy: a mutation-independent treatment[J]. Curr. Opin. Pulm. Med., 2016, 22(6): 602-609.
3	ENSINCK M M, CARLON M S. One size does not fit all: the past, present and future of cystic fibrosis causal therapies[J/OL]. Cells, 2022, 11(12): 1868[2024-07-22]. .
4	DRUMM M L, POPE H A, CLIFF W H, et al.. Correction of the cystic fibrosis defect in vitro by retrovirus-mediated gene transfer[J]. Cell, 1990, 62(6): 1227-1233.
5	JOHNSON L G, OLSEN J C, SARKADI B, et al.. Efficiency of gene transfer for restoration of normal airway epithelial function in cystic fibrosis[J]. Nat. Genet., 1992, 2(1): 21-25.
6	ZABNER J, COUTURE L A, GREGORY R J, et al.. Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis[J]. Cell, 1993, 75(2): 207-216.
7	JOSEPH P M, O'SULLIVAN B P, LAPEY A, et al.. Aerosol and lobar administration of a recombinant adenovirus to individuals with cystic fibrosis. I. methods, safety, and clinical implications[J]. Hum. Gene Ther., 2001, 12(11): 1369-1382.
8	GUGGINO W B, CEBOTARU L. Adeno-associated virus (AAV) gene therapy for cystic fibrosis: current barriers and recent developments[J]. Expert Opin. Biol. Ther., 2017, 17(10): 1265-1273.
9	FLOTTE T R. Size does matter: overcoming the adeno-associated virus packaging limit[J]. Respir. Res., 2000, 1(1): 16-18.
10	ALTON E W F W, ARMSTRONG D K, ASHBY D, et al.. Repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis: a randomised, double-blind, placebo-controlled, phase 2b trial[J]. Lancet Respir. Med., 2015, 3(9): 684-691.
11	CECCALDI R, RONDINELLI B, D'ANDREA A D. Repair pathway choices and consequences at the double-strand break[J]. Trends Cell Biol., 2016, 26(1): 52-64.
12	LIEBER M R. The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway[J]. Annu. Rev. Biochem., 2010, 79: 181-211.
13	PAQUET D, KWART D, CHEN A, et al.. Efficient introduction of specific homozygous and heterozygous mutations using CRISPR/Cas9[J]. Nature, 2016, 533(7601): 125-129.
14	BÉTERMIER M, BERTRAND P, LOPEZ B S. Is non-homologous end-joining really an inherently error-prone process?[J/OL]. PLoS Genet., 2014, 10(1): e1004086[2024-07-22]. .
15	DHEYER W, EHMSEN K T, LIU J. Regulation of homologous recombination in eukaryotes[J]. Annu. Rev. Genet., 2010, 44: 113-139.
16	FU Y, FODEN J A, KHAYTER C, et al.. High-frequency off-target mutagenesis induced by CRISPR-Cas nucleases in human cells[J]. Nat. Biotechnol., 2013, 31(9): 822-826.
17	KOBLAN L W, ARBAB M, SHEN M W, et al.. Efficient C·G-to-G·C base editors developed using CRISPRi screens, target-library analysis, and machine learning[J]. Nat. Biotechnol., 2021, 39(11): 1414-1425.
18	DOMAN J L, SOUSA A A, RANDOLPH P B, et al.. Designing and executing prime editing experiments in mammalian cells[J]. Nat. Protoc., 2022, 17(11): 2431-2468.
19	SCHWANK G, KKOO B, SASSELLI V, et al.. Functional repair of CFTR by CRISPR/Cas9 in intestinal stem cell organoids of cystic fibrosis patients[J]. Cell Stem Cell, 2013, 13(6): 653-658.
20	YAN Z, VORHIES K, FENG Z, et al.. Recombinant adeno-associated virus-mediated editing of the G551D cystic fibrosis transmembrane conductance regulator mutation in ferret airway basal cells[J]. Hum. Gene Ther., 2022, 33(19-20): 1023-1036.
21	SANZ D J, HOLLYWOOD J A, SCALLAN M F, et al.. Cas9/gRNA targeted excision of cystic fibrosis-causing deep-intronic splicing mutations restores normal splicing of CFTR mRNA[J/OL]. PLoS ONE, 2017, 12(9): e0184009[2024-07-22]. .
22	SUZUKI K, TSUNEKAWA Y, HERNANDEZ-BENITEZ R, et al.. In vivo genome editing via CRISPR/Cas9 mediated homology-independent targeted integration[J]. Nature, 2016, 540(7631): 144-149.
23	GEURTS M H, DE POEL E, AMATNGALIM G D, et al.. CRISPR-based adenine editors correct nonsense mutations in a cystic fibrosis organoid biobank[J]. Cell Stem Cell, 2020, 26(4): 503-510.
24	KRISHNAMURTHY S, TRAORE S, COONEY A L, et al.. Functional correction of CFTR mutations in human airway epithelial cells using adenine base editors[J]. Nucleic Acids Res., 2021, 49(18): 10558-10572.
25	GEURTS M H, POEL E D, PLEGUEZUELOS-MANZANO C, et al.. Evaluating CRISPR-based prime editing for cancer modeling and CFTR repair in organoids[J/OL]. Life Sci. Alliance, 2021, 4(10): e202000940[2024-07-22]. .
26	权春菊,郑忠亮.CRISPR/Cas及其衍生编辑技术在基因治疗中的应用进展[J].生物技术进展,2021,11(4):518-525.
	QUAN C J, ZHENG Z L. Application progress of CRISPR/cas and its derivative editing technology in gene therapy[J]. Curr. Biotechnol., 2021, 11(4): 518-525.
27	CHU C S, TRAPNELL B C, CURRISTIN S M, et al.. Extensive posttranscriptional deletion of the coding sequences for part of nucleotide-binding fold 1 in respiratory epithelial mRNA transcripts of the cystic fibrosis transmembrane conductance regulator gene is not associated with the clinical manifestations of cystic fibrosis[J]. J. Clin. Investig., 1992, 90(3): 785-790.
28	JIANG Q, ENGELHARDT J F. Cellular heterogeneity of CFTR expression and function in the lung: implications for gene therapy of cystic fibrosis[J]. Eur. J. Hum. Genet., 1998, 6(1): 12-31.
29	DAVIS J D, WYPYCH T P. Cellular and functional heterogeneity of the airway epithelium[J]. Mucosal Immunol., 2021, 14(5): 978-990.
30	SHAH V S, CHIVUKULA R R, LIN B, et al.. Cystic fibrosis and the cells of the airway epithelium: what are ionocytes and what do they do?[J]. Annu. Rev. Pathol., 2022, 24(17): 23-46.
31	OKUDA K, DANG H, KOBAYASHI Y, et al.. Secretory cells dominate airway CFTR expression and function in human airway superficial epithelia[J]. Am. J. Respir. Crit. Care Med., 2021, 203(10): 1275-1289.
32	R-JSHEI, PEABODY J E, KAZA N, et al.. The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis[J]. Curr. Opin. Pharmacol., 2018, 43: 152-165.
33	WU D, BOUCHER R C, BUTTON B, et al.. An integrated mathematical epithelial cell model for airway surface liquid regulation by mechanical forces[J]. J. Theor. Biol., 2018, 438: 34-45.
34	YOSHIMURA K, NAKAMURA H, TRAPNELL B C, et al.. Expression of the cystic fibrosis transmembrane conductance regulator gene in cells of non-epithelial origin[J]. Nucleic Acids Res., 1991, 19(19): 5417-5423.
35	QUESADA R, DUTZLER R. Alternative chloride transport pathways as pharmacological targets for the treatment of cystic fibrosis[J]. J. Cyst. Fibros., 2020, 19(S1): 37-41.
36	BLACONÀ G, RASO R, CASTELLANI S, et al.. Downregulation of epithelial sodium channel (ENaC) activity in cystic fibrosis cells by epigenetic targeting[J/OL]. Cell. Mol. Life Sci., 2022, 79(5): 257[2024-07-22]. .
37	DEAN C H, SNELGROVE R J. New rules for club development: new insights into human small airway epithelial club cell ontogeny and function[J]. Am. J. Respir. Crit. Care Med., 2018, 198(11): 1355-1356.
38	DONNELLEY M, PARSONS D W. Gene therapy for cystic fibrosis lung disease: overcoming the barriers to translation to the clinic[J/OL]. Front. Pharmacol., 2018, 9: 1381[2024-07-22]. .
39	CMIELEWSKI P, DONNELLEY M, PARSONS D W. Long-term therapeutic and reporter gene expression in lentiviral vector treated cystic fibrosis mice[J]. J. Gene Med., 2014, 16(9-10): 291-299.
40	BOUTIN S, MONTEILHET V, VERON P, et al.. Prevalence of serum IgG and neutralizing factors against adeno-associated virus (AAV) types 1, 2, 5, 6, 8, and 9 in the healthy population: implications for gene therapy using AAV vectors[J]. Hum. Gene Ther., 2010, 21(6): 704-712.
41	VERDERA H C, KURANDA K, MINGOZZI F. AAV vector immunogenicity in humans: a long journey to successful gene transfer[J]. Mol. Ther., 2020, 28(3): 723-746.
43	WEI T, SUN Y, CHENG Q, et al.. Lung SORT LNPs enable precise homology-directed repair mediated CRISPR/Cas genome correction in cystic fibrosis models[J/OL]. Nat. Commun., 2023, 14(1): 7322[2024-07-22]. .
44	CORTI M, ELDER M, FALK D, et al.. B-cell depletion is protective against anti-AAV capsid immune response: a human subject case study[J/OL]. Mol. Ther. Meth. Clin. Dev., 2014, 1: 14033[2024-07-22]. .
45	ALLAN K M, FARROW N, DONNELLEY M, et al.. Treatment of cystic fibrosis: from gene- to cell-based therapies[J/OL]. Front. Pharmacol., 2021, 12: 639475[2024-07-22]. .
46	SHAH V S, ERNST S, TANG X X, et al.. Relationships among CFTR expression, HCO₃ ^- secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies[J]. Proc. Natl. Acad. Sci. USA, 2016, 113(19): 5382-5387.

[1]	李书翔, 安丽萍, 梁德娟, 王凯旋, 赵建国. 朊病毒病治疗方法的研究进展[J]. 生物技术进展, 2022, 12(2): 229-235.
[2]	权春菊, 郑忠亮. CRISPR/Cas及其衍生编辑技术在基因治疗中的应用进展[J]. 生物技术进展, 2021, 11(4): 518-525.
[3]	杜梦潭,刘兴健,胡小元,张志芳,李轶女. 腺相关病毒的生产方式及其在基因治疗中的应用[J]. 生物技术进展, 2019, 9(4): 326-331.
[4]	赵丽琴,席斌,彭华松. 腺相关病毒(AAV)载体研究进展[J]. 生物技术进展, 2012, 2(2): 110-115.

囊性纤维化基因治疗研究进展

Research Progress on Cystic Fibrosis Gene Therapy

RichHTML

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献 46

相关文章 4

编辑推荐

Metrics

本文评价