Ignite Creation Date:
2024-05-05 @ 5:30 PM
Last Modification Date:
2024-10-26 @ 9:32 AM
Study NCT ID:
NCT00465062
Status:
COMPLETED
Last Update Posted:
2017-07-02
First Post:
2007-04-21
Brief Title:
A Study to Evaluate and Characterize the Effect of Pharmacological Chemicals on Blood From Patients With Gaucher Disease
Sponsor:
National Institute of Neurological Disorders and Stroke NINDS
Organization:
National Institutes of Health Clinical Center CC
Study Overview
Official Title:
A Study to Evaluate and Characterize the Effect of Pharmacological Chemicals on Blood From Patients With Gaucher Disease
Status:
COMPLETED
Status Verified Date:
2008-03-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Gaucher disease is a lysosomal storage disorder resulting from a deficiency in the key enzyme b-glucocerebrosidase GCase This enzyme is responsible for breaking down a specialized type of fat molecule known as glucocerebroside in the lysosome The enzyme deficiency is caused by genetic mutations which result in the production of misfolded GCase protein The absent or defective GCase enzyme activity leads to build-up of glucocerebroside inside certain cells Over time these Gaucher cells can accumulate and may cause inflammation or damage to specific areas within the body including the liver spleen bone marrow lung and the central nervous system
AT2101 is designed to act as a pharmacological chaperone by selectively binding to the misfolded GCase After binding to the enzyme it is thought that AT2101 promotes the proper folding processing and trafficking of the enzyme from the endoplasmic reticulum to its final destination the lysosome the area of the cell where the enzyme does its work Once it reaches the lysosome the pharmacological chaperone is displaced and the enzyme can perform its normal function which is the breakdown of its natural substrate glucocerebroside
Several in vitro and in vivo preclinical studies have been conducted In these studies AT2101 increased GCase enzyme level in cells derived from Gaucher disease patients with different genetic mutations including cells with a genetic mutation associated with the neurologic form of Gaucher disease In normal mice oral administration of AT2101 resulted in a dose-dependent increase in GCase level in the liver spleen brain and lung
This study is designed to evaluate the ex vivo response to pharmacological chaperone therapy by testing blood samples from previously treated and untreated patients with Gaucher disease The study will include patients with non-neuropathic Gaucher disease type I and neuropathic Gaucher disease types II andor III Up to 50 patients will be enrolled at the NIH
All subjects will participate in one study visit Clinical information will be collected retrospectively from medical records Information collected will include Gaucher disease diagnosis and history medical history family history assessments of clinical severity and genotype A blood sample will be collected and various cells will be isolated for laboratory testing and research
AT2101 is designed to act as a pharmacological chaperone by selectively binding to the misfolded GCase After binding to the enzyme it is thought that AT2101 promotes the proper folding processing and trafficking of the enzyme from the endoplasmic reticulum to its final destination the lysosome the area of the cell where the enzyme does its work Once it reaches the lysosome the pharmacological chaperone is displaced and the enzyme can perform its normal function which is the breakdown of its natural substrate glucocerebroside
Several in vitro and in vivo preclinical studies have been conducted In these studies AT2101 increased GCase enzyme level in cells derived from Gaucher disease patients with different genetic mutations including cells with a genetic mutation associated with the neurologic form of Gaucher disease In normal mice oral administration of AT2101 resulted in a dose-dependent increase in GCase level in the liver spleen brain and lung
This study is designed to evaluate the ex vivo response to pharmacological chaperone therapy by testing blood samples from previously treated and untreated patients with Gaucher disease The study will include patients with non-neuropathic Gaucher disease type I and neuropathic Gaucher disease types II andor III Up to 50 patients will be enrolled at the NIH
All subjects will participate in one study visit Clinical information will be collected retrospectively from medical records Information collected will include Gaucher disease diagnosis and history medical history family history assessments of clinical severity and genotype A blood sample will be collected and various cells will be isolated for laboratory testing and research
Detailed Description:
Gaucher disease GD is a rare lysosomal storage disorder caused by mutations in the gene encoding acid-Beta-glucosidase Beta-glucocerebrosidase GCase Gba the lysosomal enzyme that catalyzes the breakdown of the lipid glucosylceramide glucosylcerebroside GlcCer The resulting deficiency in GCase activity leads to an intracellular accumulation of the substrate GlcCer primarily in macrophage cells These lipid-laden macrophages known as Gaucher cells are the hallmark of the disease and their accumulation in the liver bone marrow and spleen elicits the clinical symptoms associated with GD
Pharmacological chaperone therapy is a novel approach to treat diseases due to protein misfoldingmistrafficking using small molecule ligands to rescue and increase the residual function of mutant proteins For lysosomal storage diseases in which the causative mutant enzymes have residual activity reversible inhibitors can act as pharmacological chaperones that specifically bind stabilize and facilitate the proper folding and trafficking of the mutant enzyme to the lysosome thereby increasing its ability to degrade the accumulated substrate
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 GCase in the endoplasmic reticulum and promoting trafficking of the enzyme to the lysosome In the lysosome when the pharmacological chaperone is displaced the enzyme can perform its normal function which is the breakdown of glucocerebroside
This study is designed primarily to evaluate and characterize the effects of AT2101 on GCase activity and other markers of disease in lymphoblast and macrophage cell lines derived from patients with GD Fifty subjects with a confirmed diagnosis of GD and a known Gba genotype will be enrolled in the trial
The study will consist of one study visit Clinical information will be collected retrospectively Collected information will include but not be limited to GD diagnosis medical history family history assessments of clinical severity and genotype Blood samples for a series of ex vivo assays will be collected Blood cell lines will be derived from the subjects blood samples and used for the ex vivo assays which will be conducted at a central laboratory
Pharmacological chaperone therapy is a novel approach to treat diseases due to protein misfoldingmistrafficking using small molecule ligands to rescue and increase the residual function of mutant proteins For lysosomal storage diseases in which the causative mutant enzymes have residual activity reversible inhibitors can act as pharmacological chaperones that specifically bind stabilize and facilitate the proper folding and trafficking of the mutant enzyme to the lysosome thereby increasing its ability to degrade the accumulated substrate
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 GCase in the endoplasmic reticulum and promoting trafficking of the enzyme to the lysosome In the lysosome when the pharmacological chaperone is displaced the enzyme can perform its normal function which is the breakdown of glucocerebroside
This study is designed primarily to evaluate and characterize the effects of AT2101 on GCase activity and other markers of disease in lymphoblast and macrophage cell lines derived from patients with GD Fifty subjects with a confirmed diagnosis of GD and a known Gba genotype will be enrolled in the trial
The study will consist of one study visit Clinical information will be collected retrospectively Collected information will include but not be limited to GD diagnosis medical history family history assessments of clinical severity and genotype Blood samples for a series of ex vivo assays will be collected Blood cell lines will be derived from the subjects blood samples and used for the ex vivo assays which will be conducted at a central laboratory
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| 07-N-0131 | None | None | None |