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Produced by the Centre for Genetics Education. Internet: http://www.genetics.edu.au

GENE THERAPY

Important points

•Genetherapyis‘theuseofgenesasmedicine’involvingthetransferofatherapeuticorworkingcopyofageneintospeciccellsofanindividualinordertorepairafaultygenecopy•Thetechniquemaybeusedtoreplaceafaultygene,ortointroduceanewgenewhosefunctionistocureortofavourablymodifytheclinicalcourseofacondition•Genetherapyisstillanexperimentaldisciplineandmuchresearchremainstobedonebeforethisapproachtothetreatmentofconditionwillrealiseitsfullpotential–Genetherapywasusedin2000byaFrenchresearchgroupinthetreatmentofaformofimmunedeciencyduetoamutationinagenelocatedontheXchromosome(SevereCombinedImmuneDeciency).Whentwoofthechildrentreateddevelopedleukaemiain2002and2003,causedwhenthevirususedtodeliverthetherapeuticgeneactivatedacancer-causinggene,theclinicaltrialswerestoppedbuthavenowbeenresumedonlyforpatientswithnoothertreatmentoptions•Thechallengeofdevelopingsuccessfulgenetherapyforanyspecicconditionisconsiderable:–Theconditioninquestionmustbewellunderstood–Theunderlyingfaultygenemustbeidentiedandaworkingcopyofthegeneinvolvedmustbeavailable–Thespeciccellsinthebodyrequiringtreatmentmustbeidentiedandaccessible–Ameansofefcientlydeliveringworkingcopiesofthegenetothesecellsmustbeavailable•Theproblemof‘genedelivery’ie.howtogettheneworreplacementgenesintothedesiredtissues,isverycomplexandchallenging.Someofthe‘vectors’fortheroleofdeliveringtheworkingcopyofthegenetothetargetcellsincludeusingharmlessvirusesandstemcells•Ingenetherapy,

only

body(somatic)cellsandnottheeggorspermcells(germcells)aretargetedfortreatment.Somaticgenetherapytreatstheindividualandhasnoimpactonfuturegenerationsaschangestothesomaticcellscannotbeinherited•Thestrongconsensusviewatpresentisthattherisksofmanipulationofthegenesintheeggorspermcellsfarexceedanypotentialbenetandshouldnotbeattempted

FACT SHEET

What is gene therapy?

Genetherapyis‘theuseofgenesasmedicine’.Itinvolvesthetransferofatherapeuticorworkinggenecopyintospeciccellsofanindividualinordertorepairafaultygenecopy.Thusitmaybeusedtoreplaceafaultygene,ortointroduceanewgenewhosefunctionistocureortofavourablymodifytheclinicalcourseofacondition.Thescopeofthisnewapproachtothetreatmentofaconditionisbroad,withpotentialinthetreatmentofmanygeneticconditions,someformsofcancerandcertainviralinfectionssuchasAIDS.Genetherapyremainsanexperimentaldisciplinehoweverandmuchresearchremainstobedonebeforethisapproachtothetreatmentofcertainconditionswillrealiseitsfullpotential.ThemajorityofclinicalgenetherapytrialsarebeingconductedintheUnitedStatesandEurope,withonlyamodestnumberinitiatedinothercountries,includingAustralia.Themajorityofthesetrialsfocusontreatingacquiredconditionssuchascancer.TheonlygenetherapythathasbeenapprovedforroutinetreatmentsofarisforaformofcancerwhichwasapprovedinChinainearly2004.Aformofimmunedeciencycalledadenosinedeaminase(ADA)deciencywastherstconditiontobetreatedwithagenetherapyapproachinhumansintheearly1990s.Itisalsotherstconditionforwhichtherapeuticgenetransferintostemcells(seelater)hasbeenattemptedintheclinicalarena(CandottiF,2001).

A case study of gene therapy for a genetic condition

AnotherformofimmunedeciencyisduetoamutationinagenelocatedontheXchromosomeandiscalledSevereCombinedImmuneDeciency(SCID).This‘X-linkedcondition’onlyaffectsboys(seeGeneticsFactSheet10foranexplanationoftheinheritancepatternofgeneslocatedontheXchromosome).Theuseofgenetherapyin2000inthetreatmentofthisconditionbyaFrenchresearchgroupledbyM.Cavazzana-Calvowashailedastherstexampleofageneticconditionbeingsuccessfullytreatedbygenetherapyandisamilestoneinmedicalhistory.•Sevenoutofteninfantstreatedtodatehaverestoredimmunefunction.Twoofthechildrentreatedbythegenetherapyhoweverdevelopedleukaemiain2002and2003,causedwhenthevirususedtodeliverthetherapeuticgeneactivatedacancer-causinggene(an

oncogene

–seeGeneticsFactSheet47)•Theclinicaltrialswerehaltedbuthavenowbeenresumedonlyforpatientswithnoothertreatmentoptions•Thisexperienceillustratestheneedforthistherapytobeconductedaspartofclinicaltrials

How is gene therapy carried out?

Thechallengeofdevelopingsuccessfulgenetherapyforanyspecicconditionisconsiderable.Theconditioninquestionmust

www.genetics.edu.au

bewellunderstoodandtheunderlyingfaultygeneidentied.Aworkingcopyofthegeneinvolvedmustbeavailable,thespeciccellsinthebodyrequiringtreatmentmustbeidentiedandaccessibleandnally,ameansofefcientlydeliveringworkingcopiesofthegenetothesecellsmustbeavailable.Ofallthesechallenges,theonethatismostdifcultistheproblemof‘genedelivery’ie.howtogettheneworreplacementgenesintothedesiredtissues.Someofthe‘vectors’fortheroleofdeliveringtheworkingcopyofthegenetothetargetcellsincludeusing:

a) Harmless viruses

Oneofthemostpromisingmethodscurrentlybeingdevelopedistheuseofharmlessvirusesthatcanbeusedtocarrygenesintocells.Scientistsnowhavetheknowledgeandskillstoremovethevirus’owngenesandtoreplacethemwithworkinghumangenes.Thesealteredvirusescanthenbeusedtosmugglegenesintocellswithgreatefciency.Whenvirusesareusedinthiswaytheyareknownasvectors.Someofthesevectorsarecapableofnotonlycarryingthegeneintothecellbutalsoofinsertingthegeneintothegeneticmake-upofthecell.Onceintherightlocationwithinthecellofanaffectedperson,thetransplantedgeneis‘switchedon’.Thetransplantedgenecanthenissuetheinstructionsnecessaryforthecelltomaketheproteinthatwaspreviouslymissingoraltered.

b) Stem cells

Anothertechniquewithpotentialistheuseofstemcellsindeliveringgenetherapy.Stemcellsareimmaturecellsthatcandifferentiateordevelopintocellswithdifferentfunctions.Inthistechnique,stemcellsaremanipulatedinthelaboratoryinordertomakethemacceptnewgenesthatcanthenchangetheirbehaviour.Forexample,agenemightbeinsertedintoastemcellthatcouldmakeitbetterabletosurvivechemotherapy.Thiswouldbeofassistancetothosepatientswhocouldbenetfromfurtherchemotherapyfollowingstemcelltransplantation.

Ethical considerations

Whilethebodyhasmanybillionsofcells,onlyaverysmallproportionofthesecellsareinvolvedinreproduction,theprocessbywhichourgenesarehandedontofuturegenerations.Inmalesthesecellsarelocatedinthetestesandinfemales,intheovaries.Thesespecialreproductivecellsarecalled‘

germ cells

’.Allothercellsinthebody,irrespectiveofwhethertheyarebrain,lung,skinorbonecells,areknownas‘

somatic cells

’.Ingenetherapy,onlysomaticcellsaretargetedfortreatment.Thereforeanychangestothegenesofanindividualbygenetherapywillonlyimpactonthecellsoftheirbodyandcannotbepassedontotheirchildren.Changestothesomaticcellscannotbepassedontofuturegenerations(inherited).Somaticgenetherapytreatstheindividualandhasnoimpactonfuturegenerations.

An example of somatic gene therapy for an inherited condition

Imagine,forexample,alittleboywithhaemophilia,aconditionthatiscausedbyafaultygenethatmakeshisliverunabletomakebloodclottingfactor8(seeGeneticsFactSheet40).•Genetherapywouldinvolveputtingaworkingcopyofthegenewhichcodesforfactor8intohislivercellssothathislivercouldthenproduceadequatelevelsoffactor8•Whilethelittleboyhimselfwouldbecured,thealteredgenesinhisgermcellswouldremainunchangedandhecouldstillpassthefaultygeneontofuturegenerations

Concerns with gene therapy of the egg or sperm cells

Thepossiblegeneticmanipulationoftheeggorspermcells(germcells)remainsthesubjectofintenseethicalandphilosophicaldiscussion.Thestrongconsensusviewatpresentisthattherisksofgermlinemanipulationfarexceedanypotentialbenetandshouldnotbeattempted.

Safety considerations

Notherapy,establishedorexperimental,iswithoutsomeassociatedriskandthepotentialbenetsofnewtreatmentsmustalwaysbebalancedagainstsuchrisks.TheexperiencewithgenetherapyfortheimmunodeciencyconditionSCIDasdescribedaboveillustratestheneedforthistherapytobeconductedaspartofclinicaltrials.Safetywillappropriatelyremainanimportantconsiderationastheeldofgenetherapyevolves.

Other Genetics Fact Sheets referred to in this Fact Sheet: 10, 40, 47

GENE THERAPY

FACT SHEET