SLENCT03984227
New Signaling Pathway Targeting Systemic Lupus Erythematosus
An observational study of SLE, run by Assiut University.
Trial summary
Systemic lupus erythematosus is inflammatory autoimmune disease that affects over one million people in the United States. It has a higher prevalence and incidence rate among women compared with men, and among African Americans compared with Caucasians. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- SLE
- What is being tested?
- Taking peripheral blood samples
- How many people
- 60 participants
- Where
- No sites listed yet
- Study dates
- Jul 2019to Apr 2021
- 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 18 to 60 years
- All sexes
- Adult
Study population: - SLE diagnosed patients between (18- 60) years old will be enrolled. All participants should met at least four of the American College of Rheumatology criteria (Hochberg, 1997). Disease activity will be assessed in accordance with the SLE Disease Activity Score (SLEDAI 2000 (SLEDAI-2K) (Ward et al., 2000).
Who may be able to join
- SLE diagnosed patients between (18- 60) years old will be enrolled.
Who cannot join
- Patients with known pre-existing immunological disorders.
- Patients with known pre-existing infection.
- clinical diagnosis of cancer.
- patients diagnosed with concomitant acute myocardial infarction.
Trial locations and contacts
No sites are listed yet.
About this study
Official title: Studying of New Signaling Pathway Targeting Systemic Lupus Erythematosus
Systemic lupus erythematosus is inflammatory autoimmune disease that affects over one million people in the United States. It has a higher prevalence and incidence rate among women compared with men, and among African Americans compared with Caucasians. Despite advances in treatment, standardized mortality rates in SLE remain three times higher than in the general population. The risk of mortality is significantly increased because of renal disease, cardiovascular disease, and infection.The etiology of SLE is multifactorial, with genetic predisposition, environmental factors and epigenetic alterations are involved. However, the molecular mechanisms underlying this systemic autoimmune response remain largely unknown. A key issue in the pathogenesis of lupus is how intracellular antigens become exposed and targeted by the immune system.
Read the detailed description
Antinuclear antibodies play a direct role in pathogenesis by forming immune complexes. These complexes can either deposit in the kidney or stimulate cytokine production. Dead and dying cells can fill the blood with a plentiful supply of immune complex components in lupus. So cell death is a critical issue in the pathway to auto-reactivity. Pyroptosis is a new member of cell death list. It combines the release of pro-inflammatory mediators and nuclear molecules in a way that could drive lupus. Nod-like receptor pyrins-3, caspase-1, IL-18, and IL-1β are commonly accepted markers of pyroptosis.
Gasdermin D was recently identified as the final pyroptosis executioner downstream of inflammasome activation, and may be an attractive drug target for many diseases. GSDMD is a member of the gasdermin protein family. It was identified as a caspase substrate. Under normal cellular conditions, the C-terminus of GSDMD auto-inhibits the pore-forming activity of the N-terminus. When extracellular signals associated with pyroptosis activate inflammasomes they subsequently cleave and activate caspases-1, -4, -5, and -11. Consequently, activated caspase-1 cleaves and separates the N- and C-terminals of GSDMD. Activated GSDMD forms nanoscopic pores in the cell membrane, leading to the release of proinflammatory materials and cell swelling.
Reactive oxygen species regulates the signaling pathways in response to the changes of the intracellular and extracellular environments. However, overproduction of ROS is toxic and lead to dysfunction of cell and tissue. Oxidative stress is increased in SLE. The increased ROS could promote the release of inflammatory related signaling factors, including nod-like receptor inflammasome and nuclear factor-κB. A recent study showed that inhibition of ROS generation suppressed pyroptosis of hematopoietic stem cells. It has been widely reported that NF-kB is a critical molecular switch for cellular response to oxidative stress. NF-kB exists in the form of dimer and has been demonstrated to be involved in the development and progression of various diseases associated with inflammation, apoptosis, and proliferation. A recent study showed that NF-kB is an essential transcription factor of GSDMD.
In the recent decades, increasing evidence have revealed the roles of epigenetic dysregulation, including microRNA, in the pathogenesis of SLE. MiRNAs is a class of short non-coding RNA approximately 21-25 nucleotides in length that plays important roles in many cellular processes by regulating gene expression. MiRNAs make up a novel class of post-transcriptional gene regulators By combining with the 3' noncoding region of target gene mRNA inducing their degradation or impairing their translation.
MiR-379-5p is located at delta-like 1 homolog-deiodinase, iodothyronine 3 genomic region on 14q32.31. The DLK1-DIO3 region contains 54 miRNAs that is associated with organ development and disease pathogenesis, especially carcinogenesis. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. The over-expression of miR-379-5p blocked the arsenite induced increases of GSDMD levels effect that were reversed by up-regulation of GSDMD.
- Conditions
- SLE
- Being tested
- Taking peripheral blood samples
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Taking peripheral blood samplesGenetic
quantitative real-time polymerase chain reaction
| Study group | Role | What they receive |
|---|---|---|
| SLE patient group | SLE diagnosed patients between (18- 60) years old will be enrolled. All participants should met at least four of the American College of Rheumatology criteria (Hochberg, 1997). Disease activity will be assessed in accordance with the SLE Disease Activity Score (SLEDAI 2000 (SLEDAI-2K) (Ward et al., 2000). Receives: Genetic: Taking peripheral blood samples | |
| control group | The control group will include age and sex matched healthy volunteers Receives: Genetic: Taking peripheral blood samples |
What is being measured
The primary outcome is the main question the study is designed to answer.
determination of the expression levels of GSDMD, NF-kB and miR-379-5p in SLE group and Control group
GSDMD, NF-kB and miR-379-5p expression levels will be measured using quantitative real time PCR
Measured: 6 months
detection of the relationship between oxidative stress and pyroptosis
correlation between oxidative stress and pyroptosis and detect if there is relationship between them
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted12 Jun 2019
- Study startJul 2019 (estimated)
- Primary completionDec 2020 (estimated)
- Study completionApr 2021 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (5)Papers the sponsor has linked to this study.
- Other trials for SLEStudies of the same condition, open and under way.
- More trials run by Assiut UniversityThe 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
- Observational model
- Case-control
- Time perspective
- Retrospective
- Enrolment
- 60 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Assiut University
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Eman Ragab Mohamed Ibrahem, Assiut University
- Investigators
- Ghada M Ezzat, PhD, Principal investigator, Department of Medical Biochemistry, Faculty of Medicine, Assiut UniversityMarwa A Gaber, PhD, Principal investigator, Department of Medical Biochemistry, Faculty of Medicine, Assiut University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03984227
- Sponsor's protocol ID
- Systemic lupus erythematosus
- Status last verified
- May 2019
- First submitted
- 28 May 2019
- Last updated
- 28 Jun 2019
- Results posted
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Publications
Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, Zhang Q, Irvine BA, Cluzeau T, Sallman DA, Padron E, Komrokji R, Sokol L, Coll RC, Robertson AA, Cooper MA, Cleveland JL, O'Neill LA, Wei S, List AF. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016 Dec 22;128(25):2960-2975. doi: 10.1182/blood-2016-07-730556. Epub 2016 Oct 13.
PubMed 27737891Dang Y, Wang X, Hao Y, Zhang X, Zhao S, Ma J, Qin Y, Chen ZJ. MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. Cell Death Dis. 2018 Jan 24;9(2):106. doi: 10.1038/s41419-017-0163-8.
PubMed 29367615Li J, Xue J, Wang D, Dai X, Sun Q, Xiao T, Wu L, Xia H, Mostofa G, Chen X, Wei Y, Chen F, Quamruzzaman Q, Zhang A, Liu Q. Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1beta from human hepatic cells. Metallomics. 2019 Feb 20;11(2):483-495. doi: 10.1039/c8mt00321a.
PubMed 30643918Magna M, Pisetsky DS. The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link? Scand J Immunol. 2015 Sep;82(3):218-24. doi: 10.1111/sji.12335.
PubMed 26118732Shi G, Abbott KN, Wu W, Salter RD, Keyel PA. Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion. Front Immunol. 2017 May 8;8:522. doi: 10.3389/fimmu.2017.00522. eCollection 2017.
PubMed 28533778
Study at a glance
From the registry record, last updated by the sponsor on 28 Jun 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Studying of New Signaling Pathway Targeting Systemic Lupus Erythematosus
- ClinicalTrials.gov ID
- NCT03984227
- Acronym / sponsor ID
- Systemic lupus erythematosus
- Conditions
- SLE
- Study type
- Observational
- Recruitment status
- Unknown status
- Enrolment
- 60 participants (estimated)
- Lead sponsor
- Assiut UniversityUniversity, hospital or other
- Study start
- Jul 2019 (estimated)
- Primary completion
- Dec 2020 (estimated)
- Study completion
- Apr 2021 (estimated)
- First posted
- 12 Jun 2019 (actual)
- 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.
Systemic lupus erythematosus is inflammatory autoimmune disease that affects over one million people in the United States. It has a higher prevalence and incidence rate among women compared with men, and among African Americans compared with Caucasians. Despite advances in treatment, standardized mortality rates in SLE remain three times higher than in the general population. The risk of mortality is significantly increased because of renal disease, cardiovascular disease, and infection.The etiology of SLE is multifactorial, with genetic predisposition, environmental factors and epigenetic alterations are involved. However, the molecular mechanisms underlying this systemic autoimmune response remain largely unknown. A key issue in the pathogenesis of lupus is how intracellular antigens become exposed and targeted by the immune system.
Detailed description
Antinuclear antibodies play a direct role in pathogenesis by forming immune complexes. These complexes can either deposit in the kidney or stimulate cytokine production. Dead and dying cells can fill the blood with a plentiful supply of immune complex components in lupus. So cell death is a critical issue in the pathway to auto-reactivity. Pyroptosis is a new member of cell death list. It combines the release of pro-inflammatory mediators and nuclear molecules in a way that could drive lupus. Nod-like receptor pyrins-3, caspase-1, IL-18, and IL-1β are commonly accepted markers of pyroptosis.
Gasdermin D was recently identified as the final pyroptosis executioner downstream of inflammasome activation, and may be an attractive drug target for many diseases. GSDMD is a member of the gasdermin protein family. It was identified as a caspase substrate. Under normal cellular conditions, the C-terminus of GSDMD auto-inhibits the pore-forming activity of the N-terminus. When extracellular signals associated with pyroptosis activate inflammasomes they subsequently cleave and activate caspases-1, -4, -5, and -11. Consequently, activated caspase-1 cleaves and separates the N- and C-terminals of GSDMD. Activated GSDMD forms nanoscopic pores in the cell membrane, leading to the release of proinflammatory materials and cell swelling.
Reactive oxygen species regulates the signaling pathways in response to the changes of the intracellular and extracellular environments. However, overproduction of ROS is toxic and lead to dysfunction of cell and tissue. Oxidative stress is increased in SLE. The increased ROS could promote the release of inflammatory related signaling factors, including nod-like receptor inflammasome and nuclear factor-κB. A recent study showed that inhibition of ROS generation suppressed pyroptosis of hematopoietic stem cells. It has been widely reported that NF-kB is a critical molecular switch for cellular response to oxidative stress. NF-kB exists in the form of dimer and has been demonstrated to be involved in the development and progression of various diseases associated with inflammation, apoptosis, and proliferation. A recent study showed that NF-kB is an essential transcription factor of GSDMD.
In the recent decades, increasing evidence have revealed the roles of epigenetic dysregulation, including microRNA, in the pathogenesis of SLE. MiRNAs is a class of short non-coding RNA approximately 21-25 nucleotides in length that plays important roles in many cellular processes by regulating gene expression. MiRNAs make up a novel class of post-transcriptional gene regulators By combining with the 3' noncoding region of target gene mRNA inducing their degradation or impairing their translation.
MiR-379-5p is located at delta-like 1 homolog-deiodinase, iodothyronine 3 genomic region on 14q32.31. The DLK1-DIO3 region contains 54 miRNAs that is associated with organ development and disease pathogenesis, especially carcinogenesis. Luciferase reporter assays showed that GSDMD was a direct target of miR-379-5p. The over-expression of miR-379-5p blocked the arsenite induced increases of GSDMD levels effect that were reversed by up-regulation of GSDMD.
Study design
- Observational model
- Case-control
- Time perspective
- Retrospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| SLE patient group | – | Genetic: Taking peripheral blood samplesSLE diagnosed patients between (18- 60) years old will be enrolled. All participants should met at least four of the American College of Rheumatology criteria (Hochberg, 1997). Disease activity will be assessed in accordance with the SLE Disease Activity Score (SLEDAI 2000 (SLEDAI-2K) (Ward et al., 2000). |
| control group | – | Genetic: Taking peripheral blood samplesThe control group will include age and sex matched healthy volunteers |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Age groups
- Adult
- Study population
- - SLE diagnosed patients between (18- 60) years old will be enrolled. All participants should met at least four of the American College of Rheumatology criteria (Hochberg, 1997). Disease activity will be assessed in accordance with the SLE Disease Activity Score (SLEDAI 2000 (SLEDAI-2K) (Ward et al., 2000).
Key inclusion criteria (1 listed)
- SLE diagnosed patients between (18- 60) years old will be enrolled.
Key exclusion criteria (4 listed)
- Patients with known pre-existing immunological disorders.
- Patients with known pre-existing infection.
- clinical diagnosis of cancer.
- patients diagnosed with concomitant acute myocardial infarction.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Taking peripheral blood samplesquantitative real-time polymerase chain reaction | Genetic | SLE patient group, control group |
Primary outcome
determination of the expression levels of GSDMD, NF-kB and miR-379-5p in SLE group and Control group
Time frame: 6 months
GSDMD, NF-kB and miR-379-5p expression levels will be measured using quantitative real time PCR
detection of the relationship between oxidative stress and pyroptosis
Time frame: 6 months
correlation between oxidative stress and pyroptosis and detect if there is relationship between them
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Jun 2019.
- Results publication: PubMed 27737891Basiorka AA, McGraw KL, Eksioglu EA, Chen X, Johnson J, Zhang L, Zhang Q, Irvine BA, Cluzeau T, Sallman DA, Padron E, Komrokji R, Sokol L, Coll RC, Robertson AA, Cooper MA, Cleveland JL, O'Neill LA, Wei S, List AF. The NLRP3 inflammasome functions as a driver of the myelodysplastic syndrome phenotype. Blood. 2016 Dec 22;128(25):2960-2975. doi: 10.1182/blood-2016-07-730556. Epub 2016 Oct 13.
- Results publication: PubMed 29367615Dang Y, Wang X, Hao Y, Zhang X, Zhao S, Ma J, Qin Y, Chen ZJ. MicroRNA-379-5p is associate with biochemical premature ovarian insufficiency through PARP1 and XRCC6. Cell Death Dis. 2018 Jan 24;9(2):106. doi: 10.1038/s41419-017-0163-8.
- Results publication: PubMed 30643918Li J, Xue J, Wang D, Dai X, Sun Q, Xiao T, Wu L, Xia H, Mostofa G, Chen X, Wei Y, Chen F, Quamruzzaman Q, Zhang A, Liu Q. Regulation of gasdermin D by miR-379-5p is involved in arsenite-induced activation of hepatic stellate cells and in fibrosis via secretion of IL-1beta from human hepatic cells. Metallomics. 2019 Feb 20;11(2):483-495. doi: 10.1039/c8mt00321a.
- Results publication: PubMed 26118732Magna M, Pisetsky DS. The Role of Cell Death in the Pathogenesis of SLE: Is Pyroptosis the Missing Link? Scand J Immunol. 2015 Sep;82(3):218-24. doi: 10.1111/sji.12335.
- Results publication: PubMed 28533778Shi G, Abbott KN, Wu W, Salter RD, Keyel PA. Dnase1L3 Regulates Inflammasome-Dependent Cytokine Secretion. Front Immunol. 2017 May 8;8:522. doi: 10.3389/fimmu.2017.00522. eCollection 2017.
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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.
Ghada M Ezzat, PhD principal investigator
Department of Medical Biochemistry, Faculty of Medicine, Assiut University
Marwa A Gaber, PhD principal investigator
Department of Medical Biochemistry, Faculty of Medicine, Assiut University
Questions about this trial
What is this clinical trial studying?
An observational study of SLE, run by Assiut University.
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 1 inclusion and 4 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: status not confirmed, as of the sponsor's last update on 28 Jun 2019. Status can change between updates, so confirm with the study contact before making plans.
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?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Eman R Mohamed, MD (01064006642, mervatragab224@gmail.com), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
determination of the expression levels of GSDMD, NF-kB and miR-379-5p in SLE group and Control group (time frame: 6 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03984227, which also lists 5 linked publications.
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 28 Jun 2019.