A STUDY OF INTRATHECAL ENZYME REPLACEMENT THERAPY FOR SPINAL CORD COMPRESSION

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 粘多糖样变性I（MPS I）是一种遗传性疾病，涉及称为α-L-艾杜糖醛酸酶的酶（体内的一种蛋白质）缺乏，需要这种酶来分解在全身发现的一种物质（糖胺聚糖或GAG）。 如果没有这种所需的酶，随着年龄的增长，GAG在整个身体中积累。 如果不进行治疗，这种疾病会逐渐变得更加虚弱，最终导致死亡，最严重的（Hurler）类型通常在10岁时死亡。 在不太严重的疾病形式（Hurler-Scheie和Scheie综合征）中，智力接近正常到正常，但严重的残疾可能是由压迫脊髓的GAG积累引起的。 他们也可能有增加的液体在大脑中称为“脑积水”，这可能会导致智力和痛苦的头痛迅速下降。 这些问题的治疗通常包括手术以减轻脊髓中的压力和大脑中的额外液体。 在严重的Hurler形式的疾病中，自1981年以来一直使用骨髓移植，并已被证明可以改善身体疾病的某些方面。 它还可以预防一些在2岁之前接受治疗的患者的严重智力迟钝。 这是一个危险的过程，死亡率为10- 50%，失败是常见的。 骨髓移植也不是每个人都能得到的，因为通常很难找到合适的捐赠者。 酶替代疗法（ERT）最近可用于治疗MPS I患者。 这是一种方法，以回馈他们因疾病而丢失的酶的制造形式。 每周在静脉中给予，它减少了GAG的储存，并有助于疾病中出现的许多问题。 然而，在静脉中给予，ERT不会到达大脑或脊髓以帮助解决那里的问题。 出于这个原因，在动物中研究了鞘内方法（将酶直接注射到脊髓液中，脊髓液是包围大脑和脊髓的液体）。 患有MPS I的狗接受了将酶鞘内注射到脊髓液中。这在大脑和脊髓中产生高于正常水平的艾杜糖醛酸酶。注射将大脑中的GAG储存带到正常水平。治疗还使脊髓周围组织中的GAG蓄积减少57%（Kakkis et al. 2004）。 这些组织在许多患者中引起脊髓压迫。对狗的研究表明，如果每三个月给药一次，这种鞘内治疗是有效的（Dickson等，出版中）。 本研究是在人MPS I中进行鞘内ERT的初步试验。 本研究的目的是使用每月一次的鞘内rhIDU减少患有MPS I的人类受试者的脊髓压迫。脊髓压迫可能会导致衰弱症状，如疼痛，行走困难，手或手臂使用困难，尿失禁或大便失禁。 目前这种情况的治疗方案包括支持性措施，如手术干预和疼痛的药物管理。鞘内注射rhIDU可通过减少引起压迫的物质（糖胺聚糖）的储存来为脊髓压迫提供更确定的治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mucopolysaccharidosis I (MPS I) is a hereditary disease involving deficiency of an enzyme (a type of protein in the body) called alpha-L-iduronidase, which is needed to break down a type of substance (glycosaminoglycans or GAGs) found throughout the body. Without this needed enzyme, the GAGs accumulate throughout the body with age. Without treatment, the disease becomes progressively more debilitating and eventually results in death, usually by age 10 years for the most severe (Hurler) type. In the less severe forms of the disease (Hurler-Scheie and Scheie syndromes), intelligence is near-normal to normal, but substantial disability can be caused by GAG accumulation pressing on the spinal cord. They can also have increased fluid in the brain called "hydrocephalus" which can cause a rapid decrease in intelligence and painful headaches. Treatment of these problems often include surgery to relieve the pressure in the spinal cord and from the extra fluid in the brain. In the severe Hurler form of the disease, bone marrow transplantation has been used since 1981 and has been shown to improve some aspects of the physical disease. It can also prevent severe mental retardation in some patients who are now treated before age 2 years. It is a risky procedure, with a death rate of 10-50%, and failure is common. Bone marrow transplantation is also not available for everyone, as it is frequently difficult to find a suitable donor. Enzyme replacement therapy (ERT) recently became available for the treatment of MPS I patients. This is a way to give back a manufactured form of the enzyme that they are missing due to the disease. Given in the vein every week, it reduced GAG storage and helps many of the problems seen in the disease. However, given in the vein, ERT does not reach the brain or spinal cord to help with the problems there. For that reason, an intrathecal approach (injecting the enzyme directly into the spinal fluid, which is the fluid that surrounds the brain and spinal cord), was studied in animals. Dogs with MPS I received intrathecal injections of enzyme into the spinal fluid. This produced higher than normal levels of iduronidase in the brain and spinal cord. The injections brough the GAG storage in the brain to normal levels. Treatment also achieved a 57% reduction in GAG storage in the tissues surrounding the spinal cord (Kakkis et al. 2004). These ar ethe same tissues that cause spinal cord compression in many patients. Studies in the dogs show that this intrathecal treatment is effective if given once every three months (Dickson et al in press). This study is an initial trial of intrathecal ERT in human MPS I. The goal of this study is to reduce spinal cord compression in human subjects with MPS I using monthly intrathecal rhlDU. Spinal cord compression may cause debilitating symptoms such as pain, difficulty walking, difficulty using the hands or arms, and incontinence of urine or stool. Currently treatment options for this condition include supportive measure such as surgical intervention and medical managment of pain. Intrathecal rhlDU may provide a more definitive therapy for spinal cord compression by reducing storage of the substances causing the compression (glycosaminoglycans).