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.ABSTRACT Gaucher disease is a lysosomal storage disorder caused by diminished activity of a key metabolic enzyme, glucocerebrosidase (Gcase). The reduced activity of Gcase leads to the accumulation of glycosphingolipids called glucocerebrosides inside the lysosomes in macrophages of the liver, bone marrow, and spleen. Patients with Gaucher disease exhibit hematological manifestations such as anemia and thrombocytopenia, as well as hepatosplenomegaly, skeletal impairment, and neurological impairment(in some cases). The symptoms, severity, and age of onset depend in part on the mutations and the underlying disease; over 200 mutations in the Gba gene have been identified, but four mutations are found in the majority of patients. Two of these mutations, N370S and L444P, are amino acid substitutions that are found in approximately 80% of the Gaucher population. The other two mutations (84insG and IVS2) are insertion and deletion mutations, respectively. Current treatment options for Gaucher disease include enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). These therapies have been shown to address the major hematological defects and reduce organ volume in most patients. However, neither is approved to treat the neurological symptoms or skeletal symptoms of Gaucher disease.AT2101 (isofagomine [IFG] tartrate) is an iminosugar that functions as a selective pharmacological chaperone of Gcase that is less stably folded as a result of missense mutations. Current data suggest that AT2101 may work by stabilizing mutant forms of Gcase in the endoplasmic reticulum and promotes proper trafficking of the enzyme to the lysosome. In the lysosome, when the pharmacological chaperone dissociates from the enzyme, the enzyme can perform its normal function, which is the breakdown of glucocerebrosides (GlcCer). Experiments have shown that treatment with AT2101 increases Gcase total cellular enzyme levels in vitro, increases Gcase trafficking to the lysosomes in fibroblasts of Gaucher patients, increases tissue Gcase activity and reduces plasma levels of chitinase and immunoglobulin G (IgG) in a mouse model of Gaucher disease. These results strongly support the use of AT2101 in patients with Gaucher disease resulting from missense mutations in the Gba gene.HYPOTHESIS The pharmacologic chaperone AT2101 will function as an in vivo stabilizer of mutant glucocerebrosidase and result in increased enzyme activity in patients with type 1 Gaucher disease.
SPECIFIC AIMS The primary objective of the study is to evaluate the safety and tolerability of multiple dose levels and multiple dosing regimens of orally administered AT2101 in adult patients with type 1 Gaucher disease.Primary Endpoints:'Physical examination'Vital signs'Clinical laboratory tests'ECG'Adverse events'Changes in concomitant medicationsThe secondary objective of the study is to assess pharmacodynamic effects of multiple dose levels and multiple dosing regimens of orally administered AT2101 in adult patients with type 1 Gaucher disease.Secondary Endpoints:'Beta-glucocerebrosidase (Gcase) levels in white blood cells'Glucocerebroside (GlcCer) levels in white blood cells'Chitotriosidase activity in plasma'Pulmonary and activation regulated chemokine (PARC) activity in plasmaBACKGROUND AND SIGNIFICANCE AT2101 (isofagomine [IFG] tartrate) is an iminosugar that functions as a selective pharmacological chaperone of Gcase that is less stably folded as a result of missense mutations. Current data suggest that AT2101 may work by stabilizing mutant forms of GCase in the endoplasmic reticulum and promotes proper trafficking of the enzyme to the lysosome. In the lysosome, when the pharmacological chaperone dissociates from the enzyme, the enzyme can perform its normal function, which is the breakdown of glucocerebrosides (GlcCer). Experiments have shown that treatment with AT2101 increases GCase trafficking to the lysosome in fibroblasts of Gaucher patients, increases tissue Gcase activity and reduces plasma levels of chitinase and immunoglobulin in a mouse model of Gaucher disease. These results strongly support the use of AT2101 in patients with Gaucher disease resulting from missense mutations in the Gba gene. Amicus intends to develop AT2101 for the treatment of patients with type 1, 2, or 3 Gaucher disease, irrespective of treatment history, who show visceral, hematological, skeletal, and/or neurological manifestations of the disease.
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