The humoral immune response to recombinant enzyme in mucopolysaccharidosis I

描述（由申请方提供）：溶酶体贮积症粘多糖样沉积症I（MPS I，也称为Hurler、Hurler-Scheie或Scheie综合征）可导致毁灭性的身体和神经系统疾病，通常始于儿童期，并导致严重残疾和早期死亡。MPS I患者可通过终身静脉注射重组人酶（酶替代疗法，或ERT）进行部分治疗。然而，存在持续的疾病负担，包括使人衰弱的脊柱和关节畸形、导致梗死的动脉狭窄以及瓣膜和心肌心脏病。的能力 ERT治疗这些疾病可能受到宿主针对重组蛋白产生的体液免疫应答（HIR）的限制，导致宿主细胞对酶的吸收较差。在此，我们建议在存在和不存在HIR的情况下研究酶重组人α-L-艾杜糖醛酸酶（rhIDU）在MPS I小鼠中的作用。我们的假设是，不存在HIR将改善静脉注射rhIDU的分布和疗效，即使在生命早期开始rhIDU，HIR也很重要。组织和细胞 将在16周龄MPS I小鼠中评价rhIDU的分布，这些小鼠未经rhIDU给药或经12周静脉rhIDU致敏后发生HIR。我们将使用低分子量荧光团标记的rhIDU来检验我们的假设，即HIR改变了rhIDU的分布，使其优先被网状内皮细胞和组织摄取。为了研究在存在和不存在HIR的情况下早期静脉注射rhIDU的长期影响，免疫缺陷（NOD-SCID）MPS I小鼠将在存在或不存在外源性给予的抗人α-L-艾杜糖醛酸酶免疫球蛋白G（IgG）的情况下接受rhIDU 2天至52周。将通过评价溶酶体蓄积、形态学和功能标志物来测量抗体改变rhIDU疗效的能力，假设在不存在抗体的情况下，早期给药小鼠将显示rhIDU在心血管和骨骼系统（在人类患者中对治疗具有抗性）中的更好疗效。了解HIR在ERT治疗MPS I疾病中的作用将是确定人类患者的最佳治疗是否需要规避或预防rhIDU免疫应答的策略的第一步。HIR对早期治疗的MPS I疾病的影响可能对通过目前正在开发的筛查试验确定的新生儿的管理产生影响。

DESCRIPTION (provided by applicant): 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.