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.ABSTRACTHYPOTHESISThat enzyme replacement therapy will improve vital capacity, joint range of motion, and six minute walk test results in patients with MPS II.
SPECIFIC AIMS This extension study is designed to allow idursulfase recipients in the double-blind phase of Study TKT024 to continue to receive therapy on a long-term basis. Equally important, it will also allow the placebo recipients in Study TKT024 to cross-over and begin active treatment with idursulfase. The primary objective of this extension study is to collect long-term safety and clinical outcome data in MPS II patients who are receiving idursulfase therapy. To achieve this objective, safety evaluations and clinical outcomes will be conducted at 4-month intervals during the first year of the study, which is consistent with the testing in Study TKT024. In addition, clinical events reflecting long-term MPS II disease progression in patients will be monitored and documented. The secondary objective of this study is to objtain safety data on idursulfase manufactured at commercial-scale. This drug product will be administered to patients in the trial as soon as it is available for clinical use. Pharmacokinetic data on this material will also be generated from the PK studies to be conducted during the first year. The PK and safety data on the commercial-scale drug product will be analyzed separately as well as part of the complete data set.BACKGROUND AND SIGNIFICANCEThe mucopolysaccaridoses are a set of lysosomal storage disease caused by deficiencies of enzymes required to catabolize glycosaminoglycans (GAGs). As a result, GAGs accumulate in the lysosomes of the affected tissues. The clinical consequences can vary for each individual patient, but the common pathophysiology is lysosomal accumulation of GAG molecules leading to cellular engorgement, organomegaly, tissue destruction, and organ system dysfunction. The storage of GAGs is progressive; thus, the clinical syndromes are all chronic and progressive. Invariably these diseases are associated with profound and disabling morbidity as well as very early mortality. Many of these diseases are associated with death in infancy or early childhood.MPS II or Hunter Syndrome is an X-linked recessive disease caused by the deficiency of the lysosomal enzyme iduronate-2-sulfatase (I2S), I2S functions to cleave O-linked sulfate moieties from both dermatan sulfate and heparan sulfate; therefore, due to the deficiency of I2S, these molecules progressively accumulate in MPS II, MPS II is a rare disease with an estimated incidence of 1 in 162,000 live births. The clinical phenotype of MPS II is extremely heterogeneous and is due to the chronic and progressive accumulation of GAGs in nearly all cell types, tissues, and organs of the body. MPS II is characterized by GAG accumulation in the respiratory tract, heart, liver, spleen, leptomeninges, bones, joints, oropharynx, head, neck and central nervous system. Oropharyngeal and respiratory deposition of GAGs leads to severe airway obstruction due to macroglossia, supraglottic narrowing, and trachemalacia. This obstructive anatomy and physiology lead to sleep apnea and airway obstruction. Deposition of GAGs in the heart, liver, and spleen leads to organomegaly, and cardiac valves are affected as well. The bone and joint involvement leads to severe skeletal derormities and limitations of joint mobility. There is a wide spectrum of clinical severity among MPS II patients. In the most severe cases, central nervous system involvement leads to mental retardation and progressive neurologic decline. The clinical manifestations of MPS II generally lead to death in the first or second decade of life. In the less severe form of MPS II, death may occur in early adulthood, but some patients have survived into the fifth and sixth decades of life.Currently, no standard treatment exists for MPS II. Symptomatic treatment is provided, as appropriate.
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