PLATELET BIOGENESIS, INC — Department of Health and Human Services SBIR Phase I: R

Description

Platelet Biogenesis is developing a microfluidic bioreactor that reproduces key features of adult bone marrowphysiological microenvironmentto produce human plateletsPLTsPLTs are thebandaidsof the bloodstreamresponsible for clot formation and blood vessel repairLow PLT count is a significant consequence of a radiation accident or deliberate nuclear attackfor which PLTs are a critical first line therapy to prevent mortality due to uncontrolled bleedingPLT units comprisingxPLTs mLxPLTs totalare currently derived exclusively from human volunteer donorsand must be stored at or aboveoC to avoid irreversible temperature related activation aggregationRisk of bacterial viral growth during room temperature storage results in short shelf lifedaysBlood centers typically do not have more than aday PLT inventory available for transfusion under non emergency situationsand there are currently no licensed PLT therapeutics for thrombocytopenia to treat radiation exposuresTo address this major unmet need we will validate our bioreactor to generate functional PLTs from megakaryocyte progenitors at clinical scale to treat radiation induced thrombocytopeniaRITTo date we have shown thatIt is feasible to generate functional megakaryocytes and PLTs from human induced pluripotent stem cellsiPSCsa potentially unlimited source of progenitor cells which can be stored frozen for yearsandwe can improve the rate and extent of PLT production from human iPSC derived megakaryocytes above established static culture approachesIn our current bioreactor time to initiation of PLT production is reduced fromhours to immediatelythe percent of PLT producing progenitors is increased fromto more thanthe time to completion of PLT productionxPLTs perL transfusion unitis reduced fromhours tohoursand PLT morphologyultrastructure and in vitro function is comparable to and consistent with blood PLTsAimApply our existing bioreactor to producexmurine PLTs perL transfusion unit from primary megakaryocytesand assess PLT function in vitroMorphologycytoskeletal organizationgranule contentultrastructurebiomarker expressionaggregationand clot retraction of bioreactor derived PLTs will be compared to blood PLTs under resting and activated conditionsAimInfuse bdPLTs into sub lethally irradiated mice to measure bdPLT immunogenicityclearancecirculation timehemostatic activityand determine bdPLT function in vivoTo determine whether bdPLTs are functional in vivowe will assess bdPLT clearance and circulation timerelative to blood PLT controlsand test their immunogenicity in genetically distinct and isogenic mouse strainsAimDetermine bdPLT hemostatic activity and thrombus formation in an isogenic adult mouse model of RITnon GLP pilot studyTo determine whether bdPLTs can be applied to treat RITwe will assess bdPLT function in adult mice following sub lethalirradiationGy