The lysosomal storage disorder mucopolysaccharidosis I (MPS I, also called Hurler, Hurler-Scheie, or Scheie syndrome) causes devastating physical and neurological disease, usually beginning in childhood and resulting in severe disability and early death. MPS I patients can be partially treated by lifelong intravenous administration of recombinant human enzyme (enzyme replacement therapy, or ERT). However, there is a persistent disease burden including debilitating spinal and joint deformities, arterial narrowing leading to infarction, and valvular and myocardial heart disease. The ability of ERT to treat these conditions may be limited by the humoral immune response (HIR) that is produced by the host against the recombinant protein, causing the enzyme to be taken up poorly by host cells. Here, we propose to study the effects of the enzyme recombinant human alpha-L-iduronidase (rhIDU) in MPS I mice, in the presence and absence of an HIR. Our hypothesis is that the absence of an HIR will improve the distribution and efficacy of intravenous rhIDU, and that the HIR matters even when rhIDU is initiated early in life. The tissue and cellular distribution of rhIDU will be evaluated in 16-week old MPS I mice that are either naive to rhIDU or have been sensitized with 12 weeks of intravenous rhIDU to develop an HIR. We will use rhIDU labeled with a low-molecular weight fluorophore to test our hypothesis that the HIR alters the distribution of rhIDU so that it is preferentially taken up by reticuloendothelial cells and tissues. To study the long-term effects of early intravenous rhIDU in the presence and absence of an HIR, immune deficient (NOD-SCID) MPS I mice will receive rhIDU from 2 days to 52 weeks in the presence or absence of exogenously-administered immunoglobulin G (IgG) against human alpha-L- iduronidase. The ability of antibodies to alter the efficacy of rhIDU will be measured using evaluation of lysosomal storage, morphology and functional markers, with the hypothesis that in the absence of antibodies, early treated mice will show better effectiveness of rhIDU in cardiovascular and skeletal systems (which have been resistant to treatment in human patients). Understanding the role of the HIR in ERT for MPS I disease will be the first step in determining whether optimal treatment of human patients will require strategies to circumvent or prevent the immune response to rhIDU. The impact of the HIR on early-treated MPS I disease may have implications for the management of newborns identified by screening tests that are currently in development.
Research proposed here will test whether improved effectiveness resulting from early enzyme therapy for treatment of the genetic disorder, mucopolysaccharidosis I (MPS I), occurs because of a diminished humoral immune response against the enzyme. This question has implications for the management of children affected by MPS I, and is particularly important as newborn screening is being proposed for the condition.