An Extension Study of Intrathecal Enzyme Replacement for Cognitive Decline in Mucopolysaccharidosis I

粘多糖沉积症I（MPS I）是一种由于α-利杜糖醛酸酶缺乏引起的遗传性溶酶体储存病。 重组人α-L-艾杜糖醛酸酶（rhIDU）可作为laronidase（商品名 “Aldurazyme”）静脉给药，治疗MPS I引起的身体疾病。虽然部分有效， 身体疾病，静脉注射rhIDU不能治疗MPS I的神经系统症状，因为血脑 屏障防止大部分施用的蛋白质进入中枢神经系统（CNS）。 患有MPS I的患者患有进行性神经系统疾病，包括认知下降和痴呆， 以及脊髓压迫、听力和视力问题、脑积水和头痛。我们 临床前研究发现，rhIDU鞘内（IT）给药可分散在整个 神经轴，到达深部脑结构并清除MPS I犬的脑溶酶体蓄积。我们对待 少数接受IT rhIDU治疗疾病相关脊髓压迫的MPS I受试者，并发现 这种方法没有显著的安全性问题。目前，我们正在进行一项为期2年的随机研究， IT rhIDU治疗MPS I患者的认知下降，由LDN作为试点项目资助 （NCT008523580）。这一新项目将允许对试点参与者进行为期五年的扩展研究 这将使我们能够收集有关安全性和有效性的长期数据。主要安全性结局 衡量标准是治疗相关不良反应的发生率和严重程度。主要疗效结局 测量将是基线和受试者最终记忆评分之间的受试者内平均变化 访问其他重要的疗效指标是其他神经心理学领域测试分数的变化 以及3特斯拉脑磁共振成像（MRI）参数的变化，例如体积，形态， 弥散异常和白色纤维追踪。目前，还没有针对大脑的治疗方案 在MPS I患者中，除最年轻、受影响最严重的患者外， 造血干细胞移植如果成功，rhIDU鞘内注射将为 MPS I患者的临床护理。

"Mucopolysaccharidosis I (MPS I) is an inherited lysosomal storage disease due to deficiency of alpha-Liduronidase. Recombinant human alpha-L-iduronidase (rhIDU) is available as laronidase (trade name "Aldurazyme") for intravenous delivery to treat physical disease due to MPS I. While partially effective for physical disease, intravenous rhIDU does not treat neurological symptoms of MPS I, because the blood-brain barrier prevents the bulk of the administered protein from entering the central nervous system (CNS). Patients with MPS I suffer from progressive neurological disease, including cognitive decline and dementia, as well as spinal cord compression, hearing and vision problems, hydrocephalus and headaches. Our preclinical research has found that intrathecal (IT) administration of rhIDU can disperse throughout the neuraxis, reach deep brain structures and remove brain lysosomal storage in MPS I dogs. We have treated a small number of MPS I subjects with IT rhIDU for disease-related spinal cord compression and have found no significant safety concerns for this approach. Currently, we are conducting a 2-year randomized study of IT rhIDU for cognitive decline in MPS I patients, which was funded as a pilot project by the LDN (NCT008523580). This new project would permit a five-year extension study for participants in the pilot project, which would allow us to collect long-term data on safety and efficacy. The primary safety outcome measure will be the rate and severity of treatment-related adverse effects. The primary efficacy outcome measure will be the mean intra-subject change in memory score between baseline and the subject's final visit. Other important efficacy measures are changes in scores of tests of other neuropsychological domains and changes in 3 Tesla brain magnetic resonance imaging (MRI) parameters, such as volumes, morphology, diffusion abnormalities and white matter fiber tracking. Currently, there are no treatment options for the brain in MPS I patients, except for the youngest, most severely affected patients, who may be considered for hematopoietic stem cell transplantation. If successful, intrathecal rhIDU would bring major innovation to the clinical care of MPS I patients.