The humoral immune response to recombinant enzyme in mucopolysaccharidosis I

描述(由申请人提供)：溶酶体储存障碍粘多糖病I(MPS I，也称为Hurler，Hurler-Scheie，或Scheie综合征)会导致毁灭性的身体和神经疾病，通常始于儿童时期，导致严重残疾和过早死亡。MPS I患者可以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，有持续的疾病负担，包括衰弱的脊柱和关节畸形，动脉狭窄导致梗塞，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反应(HIR)的限制，导致宿主细胞对酶的摄取很差。在此，我们拟研究重组人α-L艾杜糖醛酸酶(Rh IDU)在有无HIR的情况下对MPS I小鼠的影响。我们的假设是，缺乏HIR将改善静脉注射重组人静脉注射的分布和有效性，即使在生命早期启动重组人静脉注射治疗，HIR也是重要的。组织和细胞 将评估rhIDU在16周龄MPS I小鼠中的分布，这些小鼠要么对rhIDU很幼稚，要么已经用12周的静脉注射rhIDU致敏以形成HIR。我们将使用标记了低分子量荧光团的rhIDU来验证我们的假设，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。为了研究早期静脉注射重组人IDU在有无HIR的情况下的长期效果，免疫缺陷(NOD-SCID)MPS I小鼠在有无外源性免疫球蛋白G(Ig G)存在或不存在的情况下接受2天至52周的rhIDU治疗。抗体改变rhIDU疗效的能力将通过溶酶体储存、形态和功能标记物的评估来衡量，假设在没有抗体的情况下，早期治疗的小鼠在心血管和骨骼系统(对人类患者的治疗具有耐药性)中显示出更好的rhIDU效果。了解HIR在MPS I疾病ERT中的作用将是确定人类患者的最佳治疗是否需要规避或阻止对rhIDU的免疫反应的策略的第一步。HIR对早期治疗的MPS-I疾病的影响可能会对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.