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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054242-05
Application #
7845573
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Tagle, Danilo A
Project Start
2006-09-29
Project End
2011-11-30
Budget Start
2010-06-01
Budget End
2011-11-30
Support Year
5
Fiscal Year
2010
Total Cost
$350,323
Indirect Cost
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
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Vite, Charles H; Nestrasil, Igor; Mlikotic, Anton et al. (2013) Features of brain MRI in dogs with treated and untreated mucopolysaccharidosis type I. Comp Med 63:163-73
Dickson, Patricia I; Ellinwood, N Matthew; Brown, Jillian R et al. (2012) Specific antibody titer alters the effectiveness of intrathecal enzyme replacement therapy in canine mucopolysaccharidosis I. Mol Genet Metab 106:68-72
Dickson, P I; Pariser, A R; Groft, S C et al. (2011) Research challenges in central nervous system manifestations of inborn errors of metabolism. Mol Genet Metab 102:326-38
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Newkirk, Kim M; Atkins, Rosalie M; Dickson, Patti I et al. (2011) Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy. Invest Ophthalmol Vis Sci 52:5130-5
Lyons, Jeremiah A; Dickson, Patricia I; Wall, Jonathan S et al. (2011) Arterial pathology in canine mucopolysaccharidosis-I and response to therapy. Lab Invest 91:665-74
Dickson, Patricia I; Chen, Agnes H (2011) Intrathecal enzyme replacement therapy for mucopolysaccharidosis I: translating success in animal models to patients. Curr Pharm Biotechnol 12:946-55
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