Bioavailability, Biodistribution, and CNS Toxicity of Clinical-Grade Parvovirus H1 after Intravenous and Intracerebral Injection in Rats

摘要

TheautonomousparvovirusH1(H1PV)istransmittedinrodentpopulations.Thenaturalhostistherat,inwhichH1PVinfectionispathogeniconlyinfetusesandnewborns.H1PVinfectionofhumancancercellsleadstostrongoncolyticeffectsinpreclinicalmodels.InpreparationforaclinicaltrialofH1PVinjectioninpatientswithmalignantbraintumors,H1PVhadtobepreparedtoGoodManufacturingPracticestandards,includingextensivetoxicologytestinginrats.BecausethetrialinvolvesdirectintracerebralinjectionofH1PVintothetumorandaroundtheresectioncavity,possibletoxicitytoCNStissuehadtobeinvestigated.Inaddition,quantitativebloodlevelsandthetissuedistributionofH1PVaftersingleintracerebralorintravenousinjectionweremeasured.DirectinjectionofH1PVintoratbrainat3doselevels(maximum,7.96×107pfu)didnotcauseanymacroscopicorhistologicpathology.Furthermore,H1PVinfectionofthebraindidnotaltercentralorautonomousnervoussystemfunction.H1PVDNAwasdetectedinalmostallorgansat6h,48h,and14dafterintravenousandintracerebralinjection,withthehighestlevelsinliverandspleen.H1PVconcentrationsinmostorgansweresimilarafterintravenousandintracerebralinjection,indicatinghighpermeabilityoftheblood#8211;brainbarrierforthissmallvirus.ThecurrentresultsdemonstratewideorgandistributionofH1PVafterintravenousorintracerebralinjection,confirmthatH1PVisnonpathogenicinadultratsevenafterdirectinjectionintothebrain,andformthebasisfortheongoingParvOryx01clinicaltrial.