Intrathecal enzyme therapy for mucopolysaccharidosis I

描述（由申请人提供）：粘多糖病I （MRS I）是由于缺乏酶- l -伊杜糖醛酸酶引起的溶酶体储存障碍。重组人α - l -伊杜糖醛酸酶（laronidase, Aldurazyme）的酶替代疗法已经发展起来，并帮助许多身体疾病的疾病。然而，酶替代疗法不能治疗大脑或脊髓疾病，因为这种疗法不能穿透血脑屏障进入这些区域。将酶直接注入脊髓液（鞘内）可能提供了一种直接的方法，将治疗传递到大脑和脊髓，这可以帮助许多患有MRS I的患者。患有MRS I犬模型的狗接受鞘内注射伊杜糖醛酸酶，可使中枢神经系统组织中的伊杜糖醛酸酶浓度达到异常水平，并显著改善其溶酶体储存。在这个项目的第一部分，鞘内酶替代疗法在狗身上进行了进一步的研究，以优化剂量，验证非侵入性方法来判断治疗的成功，并在非常年轻的人群中使用。该项目的第二部分涉及将狗的临床前工作转化为MRS I患者的临床试验。鞘内酶治疗将在脊髓受压患者中进行研究，脊髓受压是MRS I患者常见的一种衰弱性疾病，通常需要脊柱手术来纠正。本研究探讨了犬类MRS I的鞘内酶治疗，并转化为MRS I患者鞘内酶替代治疗的首次临床试验。

DESCRIPTION (provided by applicant): Mucopolysaccharidosis I (MRS I) is a lysosomal storage disorder due to deficiency of the enzyme alpha-L- iduronidase. Enzyme replacement therapy with recombinant human alpha-L-iduronidase (laronidase, Aldurazyme) has been developed and helps many physical ailments of the disease. However, the enzyme replacement therapy cannot treat disease of the brain or spinal cord, because the therapy cannot penetrate the blood-brain barrier to access those areas. Giving the enzyme directly into the spinal fluid (intrathecally) may provide a straightforward way to deliver the treatment to the brain and spinal cord, which could help many patients with MRS I. Dogs with the canine model of MRS I receiving intrathecal injections of iduronidase achieve supranormal concentrations of iduronidase in CNS tissues and have dramatic improvement in their lysosomal storage. In the first part of this project, intrathecal enzyme replacement therapy is further studied in dogs, for dose optimization, validation of non-invasive methods of judging the success of the treatment, and use in the very young. The second part of the project involves the translation of the preclinical work in dogs to a clinical trial in MRS I patients. Intrathecal enzyme therapy will be studied in patients with spinal cord compression, which is a debilitating condition common in MRS I patients that often requires spinal surgery to correct. This research investigates intrathecal enzyme therapy for canine MRS I with translation to the first clinical trial of intrathecal enzyme replacement therapy for MRS I patients.