肿瘤基因治疗的研究现状和展望-邓洪新

http//．biother．orgChinJCancerBiotherApr．2015Vol．22No．2doi10．3872/j．issn．1007-385X．2015．02．006··610041No．2012CB917104863No．2012AA020802No．NCET-11-0342。ProjectsupportedbytheNationalKeyBasicＲesearchProgramsofChinaNo．2012CB917104theNationalProgramsforHighTechnologyＲesearchandDevelopmentofChina863ProgramNo．2012AA020802andtheTrans-CenturyTrainingProgramFoundationforTalentsfromtheMinistryofEducationofChinaNo．NCET-11-0342。。ClinCancerＲes、HumGeneTher、MolCancerThera、IntJCancer、Int．JNanomed、BMCCancer。、ClinCancerＲes、JBiomedNanotechnol、HumGeneTherSCI40、、“863”、“973”。107。[e-mail]2011“”“973”“863”199723。HumanGeneTherapy。NatMedPNASBloodCancerＲesClinCancerＲesJImmunolJBiolChemSCI200。5030、。[e-mail]、。、、、、2/3。、、、、。、、、、。。Ｒ730．54Q789A1007-385X201502-0170-07TumorgenetherapyCurrentstatusandfutureprospectivesDenghongxinWeiYuquanStateKeyLaboratoryofBiotherapyWestChinaHospitalSichuanUniversityChengdu·071·．610041SichuanChinaAbstractGenetherapyisoneofthemostrevolutionarymedicaltechnologiesdevelopingwiththematureofthetech-niquesofrecombinantDNAandgenecloninganditisakindofbiomedicaltreatmentbasedonchanginghumangeneticmaterials．Afternearlythirtyyearsdevelopmentgenetherapyhasexpandedfromsingle-genegeneticdiseasestreatmenttothetherapyofmalignanttumorinfectiousdiseasescardiovasculardiseaseautoimmunediseasemetabolicdiseaseandothermajordiseasesandabout2/3ofthegenetherapyclinicaltrialsaredirectedtomalignanttumor．ThisarticlewillmainlyfocusonthedevelopmenthistoryofworldgenetherapyandthedevelopmentstatusoftumorgenetherapyinChinawithemphasesonthereviewsofgeneexpressionvectorgenedeliverysystemgenetherapyclinicaltrialstheresearchanddevelopmentofgenetherapymajorproductsandtheindustrializationdevelopmentofgenetherapyandtherecentkeybreakthroughsinthemalignanttumorandgeneticdiseasesgenetherapyfields．Besidesthisarticlereviewswithemphasisonthedevelopmentopportunitiesandchallengesoftumorgenetherapyinthefuturefromfiveaspectsincludinggenedeliv-eryinvivosafetyofgenetherapynewtechnologyintumorgenetherapytumorgenetherapycombinedwithotherthera-peuticmethodsandgenedetectiontechnologyunitedwithgenetherapy．Wehavereasonstobelievethatalongwiththecontinuousbreakthroughsofkeytechnologiesofgenetherapythenextfewyearswillbeanimportantperiodoftumorgenetherapeuticproductscomingtothemarketwhichprovidesnewchoicesfortheclinicaltrialsofmalignanttumor．KeywordstumorgenetherapystatusprospectChinJCancerBiother2015222170-176genetherapy20DNA、。30、、、、。2014720762/3。2004、。、。1。。20DNA、21。1968·《》。1989。1990NIHse-verecombinedimmunodeficiencydiseaseSCIDadenosinedeaminaseADA8ADA25%1。2。1999SCID-X1“”。20107NewEnglJMed9918·171·201542222。2014NewEnglJMedγ-retro-virusSIN-γcVector9SCID-X11833。2/3———“-p53”2004NatBiotech4。2008ＲPE65Leber’sⅠNewEnglJMed5-6。2009OZ1CD34+HIVHIVNatMed7。2009X-adrenoleukadystrophyALDALDABCD12ALDSicence8。Sicence2009Science“AComebackforGeneTherapy”9。2010LancetNeurol10。2011Amgen10BioVexGM-CSF———tali-mogenelaherparepvecT-VEC11。201412Pfizer2．6SparkB。。T-VECGM-CSF。T-VECⅢ12。FDA2015429T-VECT-VEC。2008ArkADV-TKCerepro。ⅡADV-TK。ⅡADV-TKCereproⅢNatBiotech13。CereproADV-TKⅢⅡADV-TK、ADV-TK369．6%19．9%ClinCancerＲes14。、、、。1989。199770～120。201472076400Ⅱ、Ⅲ。80%、、。241．3%。2/3、、、。70%、、、、、DNA、、30%．wiley．co．uk/genmed/clinicial。·271·．。20041———p53Gendicine416H101Oncorine15、CLINeovasculogenplasmid-VEGF16、LPLDGly-bera17-184、。20127EMAUniQureAAVGlyberaAAV-LDLLPLDLPLD。201319-20。3～5。2。1987B1991B。。20041GendicineCFDAp53。2005H101Oncorine。216、、13。30～40。ADV-TK2009ⅡⅢ、。E-10AⅡ21。30Ⅲ。KH901GM-CSFⅡⅢ22。EDS01Ⅱ。OrienX010HSV-1GM-CSFⅠ、。。330。。3．1、。retrovirus、adenovirus、adeno-associatedvi-rusAAV、herpessimplexvirusHSV、poxvirus、letivirus23-24DNA、、PEI、25-26。。、。。2011Nature·371·20154222JX-594。JX-594TKGM-CSF。JX-5948～10d87%JX-59427。。。CalydonPSA/E1AE1BCV787Ⅰ、。KH901hTEＲTⅡ。3．2。199918。1999SCID-X19183、。201211FDA《》、、、、、28。3．3。。。。。CＲISPＲ/Cas9、TALEN、。CＲISPＲ/Cas9NovartisCＲISPＲ/Cas929。ＲNAmicroＲNA、、。20、、ＲNA。microＲNA、、microＲNA。3．4、、、。genedirectedenzymeprodrugtherapy。“”30-31。32·471·．MDＲ1。E10A“+”ⅡE10A、/。AmgenT-VEC2015FDA。Ⅲ。T-VECAmgenMerck＆CoT-VECPD-1Ⅰ。2015。3．5、、、、、、。“”“”33。4、、、ＲNAmi-croＲNA。1BlaeseＲMCulverKWMillerADetal．Tlymphocyte-directedgenetherapyforADA-SCIDInitialtrialresultsafter4yearsJ．Science19952705235475-480．2Hacein-Bey-AbinaSHauerJLimAetal．EfficacyofgenetherapyforX-linkedseverecombinedimmunodeficiencyJ．NEnglJMed20103634355-364．3Hacein-Bey-AbinaSPaiSYGasparHBetal．Amodifiedgam-ma-retrovirusvectorforX-linkedseverecombinedimmunodeficien-cyJ．NEnglJMed2014371151407-1417．4PearsonSJiaHKandachiK．ChinaapprovesfirstgenetherapyJ．NatBiotechnol20042213-4．5BainbridgeJWBSmithAJBarkerSSetal．Effectofgenether-apyonvisualfunctioninLeber’scongenitalamaurosisJ．NEnglJMed2008358212231-2239．6MaguireAMSimonelliFPierceEAetal．SafetyandefficacyofgenetransferforLeber’scongenitalamaurosisJ．NEnglJMed2008358212240-2248．7MitsuyasuＲTMeriganTCCarrAetal．Phase2genetherapytrialofananti-HIVribozymeinautologousCD34+cellsJ．NatMed2009153285-292．8CartierNHacein-Bey-AbinaSBartholomaeCCetal．Hemato-poieticstemcellgenetherapywithalentiviralvec