Sleeping Beauty Engineered B Cells for Mucopolysaccharidosis

Project Summary Mucopolysaccharidosis type IMPS Iis an autosomal recessive storage disease caused by the absence ofL iduronidaseIDUAresulting in systemic accumulation of glycosaminoglycanGAGstorage materialshepatosplenomegalyskeletal dysplasiascardiopulmonary obstructionprogressive neurologic impairment and death by ageMPS I is currently treated by enzyme replacement therapy and by allogeneic hematopoietic stem cell transplantationbut these treatments are extraordinarily expensive and do not fully address the skeletalcardiac and neurologic manifestations of the diseaseHere we propose an entirely novel approach to the treatment of MPS IImmusoft Corpis developing genetically engineered autologous human B cells for production of iduronidase protein upon infusion into patientsThis Phase II SBIR application is based on a Phase I award to Immusoft and Discovery GenomicsIncDGIto apply DGIandapos s Sleeping BeautySBtransposon system for non viral genetic engineering and expression of human iduronidase in B cells as a novel cellular therapy for MPS IThrough this collaborationwe have demonstratedireliable SB mediated IDUA transposition and expression in primary human B cells in large scale cultureandiisignificant reduction of metabolic disease when these B cells are adoptively transferred into immunodeficient NSG MPS I miceIn this Phase II proposalwe describe plans to carry out all necessary activities supporting IND submission and initiation of clinical testing of Immusoftandapos s B cell product in MPS I patientsIn Aimwe will conduct complete proof of concept studies testing the therapeutic efficacy of IDUA expressing B cell product adoptively transferred into immunodeficient NSG MPSI miceincluding dose ranging studiesmultiple dose studiesand thorough analysis of physiological outcomes including cardiacskeletaland neurologic assessmentIn Aimwe will test the neurologic effectiveness of B cells expressing IDUA that has been modified for enhanced transit across the blood brain barrier into the central nervous systema key target for treating MPS IIn Aimwe will conduct a one year adoptive transfer study to assess the persistence of IDUA expressing B cells in NSG MPSI miceIn Aimwe will conduct complete toxicologic studies under Good Laboratory Practice conditions to determine the safety of Immusoftandapos s B cell productThese studies will provide IND enabling results essential to the development and clinical testing of Immusoftandapos s IDUA expressing B cell product for the treatment of MPS IEffectiveness of SB engineered B cells for treatment of MPS I will have substantial ramifications for future treatment of other metabolic diseases by infusion of B cells genetically engineered to express secretable protein for system wide distribution Project Narrative Lysosomal storage disorders are a rare group of inherited diseases in which patients suffer from skeletal abnormalitiesheart and breathing problemsmental retardation and deathWhile some of these diseases can be treated by protein therapy or by bone marrow transplantationthese treatments are expensive and incompletely effectiveIt is envisioned in this grant application that one way to treat these diseases would be to restore the missing gene in patientsandaposwhite blood cells as a way of providing the missing protein and restoring function in the different organs