对重组腺相关病毒基因治疗产品包装体系和分子设计的思考

卢加琪, 韦薇

中国药学杂志 ›› 2020, Vol. 55 ›› Issue (16) : 1386-1393.

PDF(4848 KB)
中国药学杂志
PDF(4848 KB)
中国药学杂志 ›› 2020, Vol. 55 ›› Issue (16) : 1386-1393. DOI: 10.11669/cpj.2020.16.014
论著

对重组腺相关病毒基因治疗产品包装体系和分子设计的思考

  • 卢加琪, 韦薇
作者信息 +

Some Thinkings on the Structural Design and Packaging System of Raav-Based Gene Therapy Products

  • LU Jia-qi, WEI Wei
Author information +
文章历史 +

摘要

目的 近年来,数个基因治疗产品批准上市,为缺乏有效治疗手段的遗传性罕见病提供了治愈的可能。其中重组腺相关病毒载体(rAAV)广泛应用于单基因遗传病。为了保证药物的安全有效,笔者对工作进行总结及思考,以期进一步完善其监管体系。方法 笔者结合相关领域的科学研究进展和已上市重组腺相关病毒rAAV产品的国际监管考虑展开论述。结果 由于不同类型的腺相关病毒在组织细胞选择性、组装及转基因表达等方面各有差异,包装系统的设计多样,生产体系和工艺复杂,其人体应用的科学评价需综合多个方面考虑。结论 本文围绕腺相关病毒包装体系、分子设计和复制型AAV的产生机制提出现阶段的评价考虑,供研发者和监管方讨论交流。

Abstract

OBJECTIVE To summarize the structural design strategy and safety assessments of rAAV packaging systems. METHODS Based on the research progress and international review experience of commercial rAAV products, the design strategy and safety assessments of rAAV packaging systems were summarized. The design strategy and safety assessments of rAAV packaging systems were summarized. RESULTS The scientific evaluation of the pharmaceutical design of rAAV for human should cover multiple aspects, because various types of AAVs differ in tissue selectivity, viral assembly, transgene expression. Meanwhile, the packaging system is diverse, and the production process is complex. CONCLUSION The considerations referring to the rAAV structure and mechanisms of producing replication-competent AAV are proposed, and we hope to improve the communications between developers and regulators.

关键词

腺相关病毒 / 基因治疗产品 / 分子设计 / 包装系统 / 复制型腺相关病毒

Key words

adeno-associated virus / gene therapy product / structural design / packaging system / replication-competent AAV

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用
卢加琪, 韦薇. 对重组腺相关病毒基因治疗产品包装体系和分子设计的思考[J]. 中国药学杂志, 2020, 55(16): 1386-1393 https://doi.org/10.11669/cpj.2020.16.014
LU Jia-qi, WEI Wei. Some Thinkings on the Structural Design and Packaging System of Raav-Based Gene Therapy Products[J]. Chinese Pharmaceutical Journal, 2020, 55(16): 1386-1393 https://doi.org/10.11669/cpj.2020.16.014
中图分类号： R917   

参考文献

[1] WANG D, TAI P, GAO G. Adeno-associated virus vector as a platform for gene therapy delivery . Nat Rev Drug Discov, 2019, 18(5): 358-378.
[2] EMA. Glybera EPAR Product Information, summary of product characteristics .2012.https://www.ema.europa.eu/en/documents/product-information/glybera-epar-product-information_en.pdf.
[3] FDA. CMC review of orignial submission, BLA125610, Luxturna . 2017 .https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/luxturna.
[4] FDA. CMC review of orignial submission, BLA125694, Zolgensma . 2019 . https://www.fda.gov/vaccines-blood-biologics/zolgensma.
[5] DAVID J D, LILIANCE T, JUDE S. Biosafety of recombinant adeno-associated virus vectors JO . Curr Gene Ther, 2013, 13(6): 434-452.
[6] DONSANTE A, MILLER D G, LI Y, et al. AAV vector integration sites in mouse hepatocellular carcinoma . Science, 2007, 317(5837): 477-481.
[7] ROSSI A, SALVETTI A. Integration of AAV vectors and insertional mutagenesis . Med Sci (Paris), 2016, 32(2): 167-174.
[8] HSER D, GOGOL-DRING A, CHEN W, et al. Adeno-associated virus type 2 wild-type and vector-mediated genomic integration profiles of human diploid fibroblasts analyzed by third-generation PacBio DNA sequencing . J Virol, 2014, 88(19): 11253-11263.
[9] NAKAI H, WU X, FUESS S, et al. Large-scale molecular characterization of adeno-associated virus vector integration in mouse liver . J Virol, 2005, 79(6): 3606-3614.
JOCELYN K. Virus used in gene therapies may pose cancer risk, dog study hints . Science, 2020, 1:1126 . https://www.sciencemag.org/news/2020/01/virus-used-gene-therapies-may-pose-cancer-risk-dog-study-hints.
CHANDLER R J, LAFAVE M C, VARSHNEY G K, et al. Vector design influences hepatic genotoxicity after adeno-associated virus gene therapy . J Clin Invest, 2015, 125(2): 870-880.
NAULT J C, DATTA S, IMBEAUD S, et al. Recurrent AAV2-related insertional mutagenesis in human hepatocellular carcinomas . Nat Genet, 2015, 47(10): 1187-1193.
BERNS K I, BYRNE B J, FLOTTE T R, et al. Adeno-associated virus type 2 and hepatocellular carcinoma? . Hum Gene Ther, 2015, 26(12): 779-781.
CLMENT N, GRIEGER J C. Manufacturing of recombinant adeno-associated viral vectors for clinical trials . Mol Ther Methods Clin Dev, 2016, 3(16002): 1-7.
THORNE B A, TAKEYA R K, PELUSO R W. Manufacturing recombinant adeno-associated viral vectors from producer cell clones . Hum Gene Ther, 2009, 20(7): 707-714.
CLARK K R, VOULGAROPOULOU F, FRALEY D M, et al. Cell lines for the production of recombinant adeno-associated virus . Hum Gene Ther, 1995, 6(10): 1329-1341.
QIAO C, WANG B, ZHU X, et al. A novel gene expression control system and its use in stable, high-titer 293 cell-based adeno-associated virus packaging cell lines . J Virol, 2002, 76(24): 13015-13027.
SCHMIDT M, AFIONE S, KOTIN R M. Adeno-associated virus type 2 Rep78 induces apoptosis through caspase activation independently of p53 . J Virol, 2000, 74(20): 9441-9450.
FLOTTE T R, TRAPNELL B C, HUMPHRIES M, et al. Phase 2 clinical trial of a recombinant adeno-associated viral vector expressing alpha1-antitrypsin: interim results . Hum Gene Ther, 2011, 22(10): 1239-1247.
URABE M, NAKAKURA T, XIN K Q, et al. Scalable generation of high-titer recombinant adeno-associated virus type 5 in insect cells . J Virol, 2006, 80(4): 1874-1885.
KOHLBRENNER E, ASLANIDI G, NASH K, et al. Successful production of pseudotyped rAAV vectors using a modified baculovirus expression system . Mol Ther, 2005, 12(6): 1217-1225.
CHEN H. Intron splicing-mediated expression of AAV rep and cap genes and production of AAV vectors in insect cells . Mol Ther, 2008, 16(5): 924-930.
ASLANIDI G, LAMB K, ZOLOTUKHIN S. An inducible system for highly efficient production of recombinant adeno-associated virus (rAAV) vectors in insect Sf9 cells . Proc Natl Acad Sci USA, 2009, 106(13): 5059-5064.
WU Y, MEI T, JIANG L, et al. Development of versatile and flexible Sf9 packaging cell line-dependent onebac system for large-scale recombinant adeno-associated virus production . Human Gene Ther Methods, 2019, 30(5): 172-183.
WU Y, JIANG L, GENG H, et al. A recombinant baculovirus efficiently generates recombinant adeno-associated virus vectors in cultured insect cells and larvae . Mol Ther Methods Clin Dev, 2018, 10:38-47.
SHIN J H, YUE Y, DUAN D. Recombinant adeno-associated viral vector production and purification . Methods Mol Biol, 2012, 798:267-284.
GIROD A, RIED M, WOBUS C, et al. Genetic capsid modifications allow efficient re-targeting of adeno-associated virus type 2 . Nat Med, 1999, 5(12): 1052-1056.
ZHONG L, LI B, MAH C S, et al. Next generation of adeno-associated virus 2 vectors: point mutations in tyrosines lead to high-efficiency transduction at lower doses . Proc Natl Acad Sci USA, 2008, 105(22): 7827-7832.
ZHANG C, YAO T, ZHENG Y, et al. Development of next generation adeno-associated viral vectors capable of selective tropism and efficient gene delivery . Biomaterials, 2016, 80:134-145.
WOOLEY D P, SHARMA P, WEINSTEIN J R, et al. A directed evolution approach to select for novel adeno-associated virus capsids on an HIV-1 producer T cell line . J Virol Methods, 2017, 250:47-54.
OGDEN P J, KELSIC E D, SINAI S, et al. Comprehensive AAV capsid fitness landscape reveals a viral gene and enables machine-guided design . Science, 2019, 366(6469): 1139-1143.
ALLAY J A, SLEEP S, LONG S, et al. Good manufacturing practice production of self-complementary serotype 8 adeno-associated viral vector for a hemophilia B clinical trial . Hum Gene Ther, 2011, 22(5): 595-604.
KINGSMAN S M, MITROPHANOUS K, OLSEN J C. Potential oncogene activity of the woodchuck hepatitis post-transcriptional regulatory element (WPRE) . Gene Ther, 2005, 12(1): 3-4.
SCHAMBACH A, BOHNE J, BAUM C, et al. Woodchuck hepatitis virus post-transcriptional regulatory element deleted from X protein and promoter sequences enhances retroviral vector titer and expression . Gene Ther, 2006, 13(7): 641-645.
ALLEN J M, DEBELAK D J, REYNOLDS T C, et al. Identification and elimination of replication-competent adeno-associated virus (AAV) that can arise by nonhomologous recombination during AAV vector production . J Virol, 1997, 71(9): 6816-6822.
MUZYCZKA N. Use of Adeno-Associated Virus as a General Transduction Vector for Mammalian Cells . 1st ed. Berlin: Curr Top Microbiol Immunol, 1992:97-129.
HALBERT C L, STANDAERT T A, AITKEN M L, et al. Transduction by adeno-associated virus vectors in the rabbit airway: efficiency, persistence, and readministration . J Virol, 1997, 71(8): 5932-5941.
WANG X S, KHUNTIRAT B, QING K, et al. Characterization of wild-type adeno-associated virus type 2-like particles generated during recombinant viral vector production and strategies for their elimination . J Virol, 1998, 72(7): 5472-5480.
SENAPATHY P, CARTER B J. Molecular cloning of adeno-associated virus variant genomes and generation of infectious virus by recombination in mammalian cells . J Biol Chem, 1984, 259(7): 4661-4666.
GROSSMAN Z, WINOCOUR E, BERNS K I. Recombination between simian virus 40 and adeno-associated virus: virion coinfection compared to DNA cotransfection . Virology, 1984, 134(1): 125-137.
QU W H, XU R A. Establishment of a reliable method for detecting the residual HEK293 host cell protein in recombinant recombinant adeno-associated virus vector . Chin Pharm J(中国药学杂志), 2016, 51(1): 52-55.
PDF(4848 KB)

Accesses

Citation

Detail
段落导航
相关文章

/

〈 〉