This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor 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 brought 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 are the 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 management of pain. Intrathecal rhlDU may provide a more definitive therapy for spinal cord compression by reducing storage of the substances causing the compression (glycosaminoglycans).

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La Biomed Research Institute/ Harbor UCLA Medical Center
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