Mucopolysaccharidosis I (MPS I) is a lysosomal storage disorder caused by a deficiency of a-L-iduronidase. The deficiency of a-L-iduronidase leads to the accumulation of the glycosaminoglycans (GAGs) heparan sulfate and dermatan sulfate in a wide variety of tissues. Currently, the only treatment available to MPS I patients is bone marrow transplantation (BMT). BMT has demonstrated efficacy in decreasing GAG storage and improving clinical outcome but restricted availability of matched donors, high cost and high morbidity and mortality limits this procedure to only a very few patients. In those BMT patients with adequate engraftment, improvements in liver and spleen storage and urinary GAG excretion over the first few months has been shown to be associated with an improved clinical outcome including less joint stiffness, decreased airway obstruction and less cardiac disease. An adequate dose of enzyme should result in enzyme activity in tissues and reduction in the level of storage product. Based on the kinetics of mannose 6-phosphate dependent uptake in cultured fibroblasts, an enzyme dose of 25,000 units/kg (~0.l mg/kg), is sufficient to raise the extracellular compartment to a concentration exceeding the Kuptake was used in the first preclinical studies. These in vivo studies demonstrated that this dose allowed a time-averaged exposure to the enzyme at concentrations equal to the Kuptake (0.7-l.0nM) for about 1 hour. The slow infusion method used for enzyme administration and the use of albumin as carrier protein were developed during the dog studies. Once antibodies against the human a-L-iduronidase have developed, the dogs are susceptible to a complement-mediated anaphylactoid reaction. By administering a low dose of 3,000 units per kg during the first hour the dogs are protected from the reaction during the second hour when the rest of the enzyme is administered. Failure to include albumin can cause a reaction, which can be prevented in subsequent infusions by its addition at 1 mg/mL. These two modifications have prevented any serious reactions in dogs.

Project Start
1998-12-01
Project End
1999-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
35
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Type
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
Hunsaker, Sanita L; Garland, Beth H; Rofey, Dana et al. (2018) A Multisite 2-Year Follow Up of Psychopathology Prevalence, Predictors, and Correlates Among Adolescents Who Did or Did Not Undergo Weight Loss Surgery. J Adolesc Health 63:142-150
Lanzieri, Tatiana M; Chung, Winnie; Leung, Jessica et al. (2018) Hearing Trajectory in Children with Congenital Cytomegalovirus Infection. Otolaryngol Head Neck Surg 158:736-744
Bollard, Catherine M; Tripic, Tamara; Cruz, Conrad Russell et al. (2018) Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. J Clin Oncol 36:1128-1139
Michalsky, Marc P; Inge, Thomas H; Jenkins, Todd M et al. (2018) Cardiovascular Risk Factors After Adolescent Bariatric Surgery. Pediatrics 141:
Lau, Chantal (2018) Breastfeeding Challenges and the Preterm Mother-Infant Dyad: A Conceptual Model. Breastfeed Med 13:8-17
Wattacheril, Julia; Lavine, Joel E; Chalasani, Naga P et al. (2017) Genome-Wide Associations Related to Hepatic Histology in Nonalcoholic Fatty Liver Disease in Hispanic Boys. J Pediatr 190:100-107.e2
El-Hattab, Ayman W; Almannai, Mohammed; Scaglia, Fernando (2017) Arginine and citrulline for the treatment of MELAS syndrome. J Inborn Errors Metab Screen 5:
Lanzieri, Tatiana M; Chung, Winnie; Flores, Marily et al. (2017) Hearing Loss in Children With Asymptomatic Congenital Cytomegalovirus Infection. Pediatrics 139:
Thakur, Neeta; Barcelo, Nicolas E; Borrell, Luisa N et al. (2017) Perceived Discrimination Associated With Asthma and Related Outcomes in Minority Youth: The GALA II and SAGE II Studies. Chest 151:804-812
Gururangan, Sridharan; Reap, Elizabeth; Schmittling, Robert et al. (2017) Regulatory T cell subsets in patients with medulloblastoma at diagnosis and during standard irradiation and chemotherapy (PBTC N-11). Cancer Immunol Immunother 66:1589-1595

Showing the most recent 10 out of 459 publications