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

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"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.