Sleeping Beauty Engineered B Cells for Mucopolysaccharidosis

DESCRIPTION provided by applicant Mucopolysaccharidosis type I MPS I is an autosomal recessive storage disease caused by the absence of L iduronidase IDUA resulting in systemic accumulation of glycosaminoglycan GAG storage materials hepatosplenomegaly skeletal dysplasias cardiopulmonary obstruction progressive neurologic impairment and death by age MPS I is currently treated by enzyme replacement therapy and by allogeneic hematopoietic stem cell transplantation but these treatments are extraordinarily expensive and do not fully address the skeletal cardiac and neurologic manifestations of the disease Here we propose an entirely novel approach to the treatment of MPS I Immusoft Corp is developing genetically engineered autologous human B cells for production of therapeutic proteins upon infusion into patients Discovery Genomics Inc DGI focuses on clinical development of the Sleeping Beauty SB transposon system for integrative gene transfer and expression Here we propose to combine Immusoftandapos s novel B cell expression platform with DGIandapos s advanced DNA mediated cellular genetic engineering technology for the purpose of expressing human IDUA from B cells in vivo as an approach to achieve systemic expression of IDUA as a treatment for MPS I This collaborative project is further strengthened by the extensive experience of DGIandapos s investigative team and colleagues at the University of Minnesota in the conduct of preclinical studies and clinical trials of new treatments for lysosomal storage diseases in particular MPS I For this Phase I study the Specific Aims are i Sleeping Beauty mediated human iduronidase gene transfer and expression in primary human B cells cultured in vitro B cells will be isolated from human blood and expanded in culture using Immusoftandapos s Immune System Programming technology Early in the expansion process cells will be collected and nucleofected with SB transposon DNA encoding human IDUA along with a plasmid encoding SB transposase to mediate integration into host B cell chromosomes ii These cells will then be infused into immunodeficient NOD SCID IDUA deficient mice evaluating recipient animals for engraftment expression and distribution of IDUA activity and correction of metabolic and neurologic disease Results from these studies will be directly applicable to the development of a clinical protocol for treatment of human MPS I by infusion of B cells genetically engineered using the SB transposon system PUBLIC HEALTH RELEVANCE Lysosomal storage disorders are a rare group of inherited diseases in which patients suffer from skeletal abnormalities heart and breathing problems mental retardation and death While some of these diseases can be treated by protein therapy or by bone marrow transplantation these treatments are expensive and incompletely effective It is envisioned in this grant application that one way to treat these diseases would be to restore the missing gene in patientsandapos white blood cells as a way of providing the missing protein and restoring function in the different organs