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.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
Project #
Application #
Study Section
Developmental Brain Disorders Study Section (DBD)
Program Officer
Tagle, Danilo A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
La Biomed Research Institute/ Harbor UCLA Medical Center
United States
Zip Code
Provenzale, James M; Nestrasil, Igor; Chen, Steven et al. (2015) Diffusion tensor imaging and myelin composition analysis reveal abnormal myelination in corpus callosum of canine mucopolysaccharidosis I. Exp Neurol 273:1-10
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
Chen, Agnes; Vogler, Carole; McEntee, Michael et al. (2011) Glycosaminoglycan storage in neuroanatomical regions of mucopolysaccharidosis I dogs following intrathecal recombinant human iduronidase. APMIS 119:513-21
Tippin, Brigette L; Troitskaya, Larisa; Kan, Shih-hsin et al. (2011) Biochemical characterization of fluorescent-labeled recombinant human alpha-L-iduronidase in vitro. Biotechnol Appl Biochem 58:391-6
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
Christensen, Bruce W; Asa, Cheryl S; Wang, Chong et al. (2011) Effect of semen collection method on sperm motility of gray wolves (Canis lupus) and domestic dogs (C. l. familiaris). Theriogenology 76:975-80

Showing the most recent 10 out of 18 publications