Adeno-associated virus vector as a platform for gene therapy ...

2024-09-21

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Adeno-associated virus (AAV) vectors are the leading platform for gene delivery for the treatment of a variety of human diseases. Skiptomaincontent Thankyouforvisitingnature.com.YouareusingabrowserversionwithlimitedsupportforCSS.Toobtain thebestexperience,werecommendyouuseamoreuptodatebrowser(orturnoffcompatibilitymodein InternetExplorer).Inthemeantime,toensurecontinuedsupport,wearedisplayingthesitewithoutstyles andJavaScript. Advertisement nature naturereviewsdrugdiscovery reviewarticles article Subjects DrugdiscoveryGenetherapy AbstractAdeno-associatedvirus(AAV)vectorsaretheleadingplatformforgenedeliveryforthetreatmentofavarietyofhumandiseases.RecentadvancesindevelopingclinicallydesirableAAVcapsids,optimizinggenomedesignsandharnessingrevolutionarybiotechnologieshavecontributedsubstantiallytothegrowthofthegenetherapyfield.PreclinicalandclinicalsuccessesinAAV-mediatedgenereplacement,genesilencingandgeneeditinghavehelpedAAVgainpopularityastheidealtherapeuticvector,withtwoAAV-basedtherapeuticsgainingregulatoryapprovalinEuropeortheUnitedStates.ContinuedstudyofAAVbiologyandincreasedunderstandingoftheassociatedtherapeuticchallengesandlimitationswillbuildthefoundationforfutureclinicalsuccess. Yourinstitutedoesnothaveaccesstothisarticle Relevantarticles OpenAccessarticlescitingthisarticle. 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Additionalaccessoptions: Login Learnaboutinstitutionalsubscriptions Fig.1:50yearsofAAV.Fig.2:DiagramofrAAVtransductionpathway.Fig.3:Infographicofthefourprimarymethodsforcapsiddiscoveryandengineering.Fig.4:OverviewofrAAVinterventionalgenetherapyclinicaltrials.Fig.5:ImmunologicalbarrierstosuccessfulrAAVgenedelivery. 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DownloadreferencesAcknowledgementsTheauthorsthankH.MaforfigureconceptsandillustrationandL.Renforcompilingdataforthetableofadeno-associatedvirus(AAV)genetherapyclinicaltrials.TheauthorsthankallmembersoftheGaolaboratoryandtheirnumerouscolleaguesforproductivecollaborationsandstimulatingdiscussionsonAAVandgenetherapy.TheyalsothankTheAmericanSocietyofGeneandCellTherapyandallmembersofthegenetherapyfieldfortheirinvaluablecontributions.Theauthorsapologizefornotbeingabletobemorecomprehensiveinreviewingalltheworkoftheircolleaguesowingtospacelimitations.ResearchintheGaolaboratoryissupportedbygrantsfromtheNationalInstitutesofHealth(NIH),theCHDIFoundation,theGraceScienceFoundationandtheauthors’industrypartners.AuthorinformationAuthornotesTheseauthorscontributedequally:DanWang,PhillipW.L.TaiAuthorsandAffiliationsHoraeGeneTherapyCenter,UniversityofMassachusettsMedicalSchool,Worcester,MA,USADanWang, PhillipW.L.Tai & GuangpingGaoLiWeiboInstituteforRareDiseasesResearch,UniversityofMassachusettsMedicalSchool,Worcester,MA,USADanWang, PhillipW.L.Tai & GuangpingGaoDepartmentofMicrobiologyandPhysiologicalSystems,UniversityofMassachusettsMedicalSchool,Worcester,MA,USADanWang, PhillipW.L.Tai & GuangpingGaoAuthorsDanWangViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarPhillipW.L.TaiViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarGuangpingGaoViewauthorpublicationsYoucanalsosearchforthisauthorin PubMed GoogleScholarCorrespondingauthorCorrespondenceto GuangpingGao.Ethicsdeclarations Competinginterests G.G.isascientificco-founderofAspaTherapeuticsandVoyagerTherapeuticsandholdsequityinthecompanies.G.G.isaninventorofpatentsrelatedtoadeno-associatedvirus(AAV)genetherapywithpotentialroyaltieslicensedtoAspaTherapeutics,VoyagerTherapeuticsandotherbiopharmaceuticalcompanies. AdditionalinformationPublisher’snoteSpringerNatureremainsneutralwithregardtojurisdictionalclaimsinpublishedmapsandinstitutionalaffiliations.Relatedlinks ClinicalTrials.gov: http://www.clinicaltrials.gov/ GlossaryVectorology AfieldofstudybasedonthebioengineeringofdeliveryvehiclesforbiomoleculessuchasDNAandRNA. Packaging Thebiologicalprocessofproducingfullyassembledvectorparticles,suchasrecombinantadeno-associatedviruses(rAAVs)consistingoftheDNAgenomewithinthecapsid. Serotypes Aclassificationsystemforcapsidsorviralstrainsestablishedbysurfaceantigens. EpisomalDNA DNAthatisautonomousfrom thehostchromosomalDNA;thetermisusedforcircularized,double-strandedadeno-associatedvirus(AAV)vectorgenomespeciesthatpersistwithinthetransducedcellnucleus. Blood–brainbarrier (BBB).Asemipermeablephysiologicalbarrierthatseparatesthecirculatingbloodfromthecentralnervoussystemandcomprisesendothelialcells,astrocytesandpericytes. Seroepidemiological Pertainingtotheepidemiologicalstudyofbloodserumantibodiesorantigensinpopulations. Codonexpansion Asyntheticbiologytechniquethatreprogrammesacodontoencodeanaminoacidthatisnotnaturallyencoded. Intraparenchymal Withinthebulkofthetissueororgan. ArtificialmicroRNAs (amiRs).MoleculartoolsthatarebasedonnaturalmicroRNAsequencesandstructuresthathouseasmallinterferingRNA(siRNA)cassettedesignedtotargetadesiredsequence. Homology-directedrepair (HDR).ADNArepairmechanisminthepresenceofahomologousDNApieceastherepairtemplate. Multiplicityofinfection Theratioofinfectiousagents(forexample,recombinantadeno-associatedvirus(rAAV))toinfectiontargets(forexample,cells). Non-homologousendjoining (NHEJ).ADNArepairmechanismthatdirectlyligatestwobrokenDNAendswithoutahomologousDNAtemplate. Adventitiousagents Anypotentiallyharmfulandunintentionallyintroducedagent(viruses,bacteria,mycoplasma,fungi,protozoa,parasites,transmissiblespongiformencephalopathies,etc.)thatmaybefoundinmanufactureddrugproducts. Genotoxicity Damagingeffectonthegenome,wherebydeleteriousmutationsarecreated. Epigenome Thecombinedchromatinstate(forexample,DNAandhistonemodificationsandnon-codingRNAassociations)throughoutthegenomeofanorganismthatimpartsheritableinfluenceovergeneexpression. RightsandpermissionsReprintsandPermissionsAboutthisarticleCitethisarticleWang,D.,Tai,P.W.L.&Gao,G.Adeno-associatedvirusvectorasaplatformforgenetherapydelivery. NatRevDrugDiscov18,358–378(2019).https://doi.org/10.1038/s41573-019-0012-9DownloadcitationPublished:01February2019IssueDate:May2019DOI:https://doi.org/10.1038/s41573-019-0012-9SharethisarticleAnyoneyousharethefollowinglinkwithwillbeabletoreadthiscontent:GetshareablelinkSorry,ashareablelinkisnotcurrentlyavailableforthisarticle.Copytoclipboard ProvidedbytheSpringerNatureSharedItcontent-sharinginitiative Furtherreading Brain-derivedneurotrophicfactorinAlzheimer’sdiseaseanditspharmaceuticalpotential LinaGao YunZhang WeihongSong TranslationalNeurodegeneration(2022) CurrentapplicationsandfutureperspectiveofCRISPR/Cas9geneeditingincancer Si-WeiWang ChaoGao Ai-WuKe MolecularCancer(2022) Treatmentofbladdercancerbygeoinspiredsyntheticchrysotilenanocarrier-deliveredcircPRMT5siRNA ChunpingYu YiZhang JianyeLiu BiomaterialsResearch(2022) TargetingthetranscriptionalactivityofSTAT3byanovelfusionprotein YanqiongChen WentingZhang YiLiu BMCCancer(2022) Therapydevelopmentforspinalmuscularatrophy:perspectivesformusculardystrophiesandneurodegenerativedisorders SibylleJablonka LuisaHennlein MichaelSendtner NeurologicalResearchandPractice(2022) Accessthroughyourinstitution Changeinstitution Buyorsubscribe AssociatedContent Special SCGE Collection Genetherapyforrarediseases Advertisement Explorecontent Researcharticles Reviews&Analysis News&Comment Videos Currentissue Collections FollowusonFacebook FollowusonTwitter Subscribe Signupforalerts RSSfeed Aboutthejournal Aims&Scope JournalInformation AbouttheEditors JournalCredits Editorialinputandchecks EditorialValuesStatement JournalMetrics Publishingmodel Editorialpolicies Contact Posters WebFeeds Conferences Publishwithus ForAuthors ForReferees Submitmanuscript Search Searcharticlesbysubject,keywordorauthor Showresultsfrom Alljournals Thisjournal Search Advancedsearch Quicklinks Explorearticlesbysubject Findajob Guidetoauthors Editorialpolicies Closebanner Close SignupfortheNatureBriefingnewsletter—whatmattersinscience,freetoyourinboxdaily. 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