OpinionRestoringthep53‘Guardian’Phenotypeinp53-DeficientTumorCellswithCRISPR/Cas9ChiraSergiu,1,*GuleiDiana,2HajitouAmin,3andBerindan-NeagoeIoana1,2,4[162_TD$DIF]Withanincreasingprevalenceinthehumanpopulation,cancerhasbecomeoneofthemostinvestigatedfieldsofmedicine.AmongthepotentialtargetsforcancertherapyisthetumorsuppressorgeneTP53,whichisfoundinamutatedstateinapproximately50%ofhumancancersandisoftenassociatedwithpoorprognosis.Weproposeanovel,highlytumor-specificdeliverysystemforTP53,basedontheCRISPR/Cas9genomeeditingtechnology.Thissystemwillrestorethenormalp53phenotypeintumorcellsbyreplacingthemutantTP53genewithafunctionalcopy,leadingtosustainedexpressionofp53proteinandtumorregression.TP53-TargetedBiotherapeuticStrategiesforCancerTreatmentCancerrepresentsaconsiderableburdenfordevelopinganddevelopedcountries,withanegativeimpactonthehealth,social,andeconomicsectors.Asoneoftheleadingcausesofmortalityworldwide[1],cancerhasgainedspecialattentioninthescientificcommunity,andfindingtreatmentsthatareeffective,safe,andselectiveisamajorgoalofcurrentanticancerresearch[2].AcommoncharacteristicofmanycancercellsisthemutationalstatusofthetumorsuppressorgeneTP53(seeGlossary),withalmosthalfofhumanmalignanciesharboringanalteredformofTP53[3].Therefore,TP53hasbecomeanimportanttherapeutictargetforcancertreatment,andmultiplestrategiesforrestoringitstumorsuppressoractivityhavebeendeveloped.ThedistributionofmutationsintheTP53genespreadsthroughoutthewholesequence,withahigherfrequencyintheDNA-bindingdomain,mostofwhicharemissensemutationsleadingtoincorrectfoldingoftheproteinandimpairmentoffunction(reviewedin[4]).MutationsintheTP53genehavealsobeenassociatedwithgain-of-functionthatcanpromotethemalignantbehavior[5].Therefore,targetingTP53mutationsrepresentsapotentialtherapeuticstrategy,thoughmanytherapiesremainproofsofconceptonly.RestoringthemutatedstateofTP53toitswildtypefunctionbyvariouscompoundscaninduceapoptosisandsenescenceincancercells,inbothinvitro[6–8]andinvivomodels[9,10].Moredetai...
