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 10. 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 iduronidase protein upon infusion into patients. This Phase II SBIR application is based on a Phase I award to Immusoft and Discovery Genomics, Inc. (DGI) to apply DGI's Sleeping Beauty (SB) transposon system for non-viral genetic engineering and expression of human iduronidase in B cells as a novel cellular therapy for MPS I. Through this collaboration, we have demonstrated; (i) reliable SB-mediated IDUA transposition and expression in primary human B cells in large scale culture, and (ii) significant reduction of metabolic disease when these B cells are adoptively transferred into immunodeficient NSG-MPS I mice. In this Phase II proposal, we describe plans to carry out all necessary activities supporting IND submission and initiation of clinical testing of Immusoft's B cell product in MPS I patients.
In Aim 1 we will conduct complete proof-of-concept studies testing the therapeutic efficacy of IDUA-expressing B cell product adoptively transferred into immunodeficient NSG-MPSI mice, including dose-ranging studies, multiple dose studies, and thorough analysis of physiological outcomes including cardiac, skeletal, and neurologic assessment.
In Aim 2 we 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 system, a key target for treating MPS I.
In Aim 3 we will conduct a one-year adoptive transfer study to assess the persistence of IDUA expressing B cells in NSG-MPSI mice.
In Aim 4 we will conduct complete toxicologic studies under Good Laboratory Practice conditions to determine the safety of Immusoft's B cell product. These studies will provide IND-enabling results essential to the development and clinical testing of Immusoft's IDUA-expressing B cell product for the treatment of MPS I. Effectiveness 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.
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 patients' white blood cells as a way of providing the missing protein and restoring function in the different organs.
