A Study to Evaluate and Characterize the Effect of Pharmacological Chemicals on Blood From Patients With Gaucher Disease
| Status: | Completed |
|---|---|
| Conditions: | Metabolic |
| Therapuetic Areas: | Pharmacology / Toxicology |
| Healthy: | No |
| Age Range: | Any |
| Updated: | 4/21/2016 |
| Start Date: | April 2007 |
| End Date: | March 2008 |
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 and/or 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.
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 and/or 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.
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
misfolding/mistrafficking 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.
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
misfolding/mistrafficking 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.
- INCLUSION CRITERIA:
To be eligible for the study, subjects must fulfill all of the following inclusion
criteria:
1. Willing and able to provide written informed consent by subject or legal guardian.
2. Male or female of any age.
3. Confirmed diagnosis of GD with known genotype.
4. Clinically stable and either treatment naive or on a stable dose of ERT and/or SRT
for at least 6 months prior to study entry.
5. Available medical records for collection of retrospective clinical information.
EXCLUSION CRITERIA:
To be eligible for the study, subjects must not fulfill any of the following exclusion
criteria:
1. Received any investigational product within 30 days prior to study entry.
2. Other significant disease or be otherwise unsuitable for the study, as determined by
the investigator.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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