Gaucher DiseaseNCT00465062
A Study to Evaluate and Characterize the Effect of Pharmacological Chemicals on Blood From Patients With Gaucher Disease
An observational study of Gaucher Disease, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
Trial 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. Read more about this study
- Who is it for?
- Any age
- Conditions the study is for
- Gaucher Disease
- How many people
- 50 participants
- Where
- 1 siteUnited States
- Study dates
- 19 Apr 2007to 3 Mar 2008
- Phase
- Observational
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages Any age
- All sexes
- No healthy volunteers
- Child, Adult, Older adult
Who may be able to join
- To be eligible for the study, subjects must fulfill all of the following inclusion criteria:
- Willing and able to provide written informed consent by subject or legal guardian.
- Male or female of any age.
- Confirmed diagnosis of GD with known genotype.
- 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.
- Available medical records for collection of retrospective clinical information.
Who cannot join
- To be eligible for the study, subjects must not fulfill any of the following exclusion criteria:
- Received any investigational product within 30 days prior to study entry.
- Other significant disease or be otherwise unsuitable for the study, as determined by the investigator.
Trial locations and contacts
1 site in 1 country.
United States1 site
National Institutes of Health Clinical Center, 9000 Rockville Pike
Bethesda, Maryland, 20892
About this study
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.
Read more
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.
Read the 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 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.
- Conditions
- Gaucher Disease
- Keywords
- Lysosomal Disease, Lipids, B Lymphocytes, Brain Damage, Gaucher Disease, GD
- Medical subject headings
- Gaucher Disease, Brain Injuries
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Apr 2007 (estimated)
- Study start19 Apr 2007
- Study completion3 Mar 2008
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Gaucher DiseaseStudies of the same condition, open and under way.
- More trials run by National Institute of Neurological Disorders and Stroke (NINDS)The sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Enrolment
- 50 participants
Sponsor and investigators
- Sponsor type
- US National Institutes of Health
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00465062
- Sponsor's protocol ID
- 070131
- Other IDs
- 07-N-0131
- Status last verified
- 3 Mar 2008
- First submitted
- 21 Apr 2007
- Last updated
- 2 Jul 2017
- Results posted
- No
Publications
Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefield LK, Morrison A, Lwin A, Colegial C, Allman JM, Schiffmann R. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab. 2004 Jul;82(3):192-207. doi: 10.1016/j.ymgme.2004.04.011.
PubMed 15234332
Study at a glance
From the registry record, last updated by the sponsor on 2 Jul 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Study to Evaluate and Characterize the Effect of Pharmacological Chemicals on Blood From Patients With Gaucher Disease
- ClinicalTrials.gov ID
- NCT00465062
- Acronym / sponsor ID
- 070131
- Conditions
- Gaucher Disease
- Keywords
- Lysosomal Disease, Lipids, B Lymphocytes, Brain Damage, Gaucher Disease, GD
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 50 participants
- Lead sponsor
- National Institute of Neurological Disorders and Stroke (NINDS)US National Institutes of Health
- Study start
- 19 Apr 2007
- Study completion
- 3 Mar 2008
- First posted
- 24 Apr 2007 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
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 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.
Study design
Who may qualify
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child, Adult, Older adult
Key inclusion criteria (6 listed)
- To be eligible for the study, subjects must fulfill all of the following inclusion criteria:
- Willing and able to provide written informed consent by subject or legal guardian.
- Male or female of any age.
- Confirmed diagnosis of GD with known genotype.
- 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.
Key exclusion criteria (3 listed)
- To be eligible for the study, subjects must not fulfill any of the following exclusion criteria:
- Received any investigational product within 30 days prior to study entry.
- Other significant disease or be otherwise unsuitable for the study, as determined by the investigator.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Not reported in the source record.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 2 Jul 2017.
- Background: PubMed 15234332Wong K, Sidransky E, Verma A, Mixon T, Sandberg GD, Wakefield LK, Morrison A, Lwin A, Colegial C, Allman JM, Schiffmann R. Neuropathology provides clues to the pathophysiology of Gaucher disease. Mol Genet Metab. 2004 Jul;82(3):192-207. doi: 10.1016/j.ymgme.2004.04.011.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
The record lists no contact. Use the official record to reach the sponsor.
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Gaucher Disease, run by National Institute of Neurological Disorders and Stroke (NINDS) at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 3 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 2 Jul 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00465062, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 2 Jul 2017.