Ignite Creation Date:
2024-05-06 @ 1:10 PM
Last Modification Date:
2024-10-26 @ 1:10 PM
Study NCT ID:
NCT03950804
Status:
UNKNOWN
Last Update Posted:
2019-08-14
First Post:
2019-05-12
Brief Title:
Transcriptome and Metabolic Analyses of CHAPLE Disease
Sponsor:
Marmara University
Organization:
Marmara University
Study Overview
Official Title:
Transcriptome and Metabolic Analyses of CHAPLE Disease Patients With or Without Eculizumab Treatment
Status:
UNKNOWN
Status Verified Date:
2019-08
Last Known Status:
RECRUITING
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:
CHAPLEOMIC
Brief Summary:
CHAPLE syndrome complement hyperactivation angiopathic thrombosis protein losing enteropathy is a newly discovered genetic disorder which is caused by deleterious mutations in the CD55 gene Patients often suffer from chronic manifestations that may lead to life-threatening complications despite conventional treatment optionsThe cause of gastrointestinal protein loss is distorted lacteals in the gut referred to as primary intestinal lymphangiectasia PIL There is a second group of patients with PIL with intact CD55 referred to here as non-CHAPLE PIL The current study aims to explore the signatures of CHAPLE and non-CHAPLE PILs discover druggable molecular targets and identify biomarkers that can direct therapy A subgroup of patients with CHAPLE syndrome receive treatment with a complement C5 blocker eculizumab on an off-label basis This study involves serial transcriptome and metabolic profiling of biological samples under eculizumab therapy and correlates them with the clinical response Overall the aim of this research is to integrate clinical data and high-throughput metabolic profiling approaches to better characterize the etiology of PILs and develop novel therapeutic approaches
Detailed Description:
CHAPLE syndrome is a newly discovered genetic disorder characterized by excessive loss of proteins in the gastrointestinal tract referred to as protein-losing enteropathy The disease typically presents in early childhood with facial and extremity edema in relation to hypoalbuminemia chronic diarrhea failure to thrive and in extreme cases severe thromboembolic disease that can lead to premature death Patients afflicted with this newly discovered disease have been treated with conventional medications including inflammatory bowel disease drugs to reduce gastrointestinal inflammation albumin and immunoglobulin replacement therapy dietary modification supportive measures to supplement micronutrients and vitamins surgery to remove affected intestinal segments among others These interventions have often provided only partial relief with no capacity to alter the natural course of the disease
CHAPLE syndrome is caused by loss of a complement regulatory protein due to deleterious mutations in the CD55 gene which results in excessive activation of the complement system Based on the scientific observations that complement hyperactivation is the primary event that underlies disease manifestations it was hypothesized that complement inhibition therapy can potentially reverse the pathological processes Through a compessionate program 3 CHAPLE patients from a single family have been treated with a complement C5 blocker antibody called eculizumab with favorable response Kurolap et al PMID 28657861 While these observations confirm the primary role of complement hyper activation in PIL associated with CHAPLE syndrome the pathogenesis of PILs not related to CD55 deficiency non-CHAPLE PIL remains unknown It is hypothesized that that there may be pathogenetic intersections between CHAPLE and non-CHAPLE PILs
Following a clinical observation that eculizumab provides a rapid clinical relief in unrelated CHAPLE patients based in Turkey similar to Kurolap et als report researchers of this study decided to evaluate the clinical outcome of eculizumab among subsequent CHAPLE patients who are placed on this therapy In parallel molecular investigations on biological samples under eculizumab therapy are being carried to dissect the key alterations under complement C5 blockade
The current study is based on use of high-throughput methods to investigate PILs including exome sequencing for the non-CHAPLE PILs transcriptomics proteome and microbiome investigations The aims of the study include 1 Discovery of signatures and biomarkers in CHAPLE 2 Identification of the molecular etiology of non-CHAPLE PILs and potentially discover novel gene defects The integrated application of genomics transcriptome proteomics and microbiome aims to identify key mediators and pathways operative in the pathogenesis of intestinal lymphangiectasias Serial evaluation and longitudinal follow up of patient samples under eculizumab anti-complement C5 antibody therapy investigates dynamic alterations in the pathological profiles in CHAPLE syndrome It is anticipiated that these studies will improve the diagnosis and treatment of CHAPLE and related conditions
Goals of the current study include
1 To discover novel gene defects underlying PILs not related to CD55 deficiency
2 To identify signatures of CHAPLE disease and non-CHAPLE PILs that may reveal key mediators of disease and additional novel therapeutic targets
3 To explore the efficacy of eculizumab in a larger group of CHAPLE patients from unrelated families with variable degree of disease severity
4 To analyze patient samples collected before and during eculizumab therapy with the following objectives
1 To understand relations between eculizumab concentration complement function CH50 AH50 and complement protein levels C3 C5 CFB C3a C5a sC5b-9 Bb Ba
2 To explore biomarkers of inflammation and thrombosis complications of the disease that can occur in certain affected individuals
CHAPLE syndrome is caused by loss of a complement regulatory protein due to deleterious mutations in the CD55 gene which results in excessive activation of the complement system Based on the scientific observations that complement hyperactivation is the primary event that underlies disease manifestations it was hypothesized that complement inhibition therapy can potentially reverse the pathological processes Through a compessionate program 3 CHAPLE patients from a single family have been treated with a complement C5 blocker antibody called eculizumab with favorable response Kurolap et al PMID 28657861 While these observations confirm the primary role of complement hyper activation in PIL associated with CHAPLE syndrome the pathogenesis of PILs not related to CD55 deficiency non-CHAPLE PIL remains unknown It is hypothesized that that there may be pathogenetic intersections between CHAPLE and non-CHAPLE PILs
Following a clinical observation that eculizumab provides a rapid clinical relief in unrelated CHAPLE patients based in Turkey similar to Kurolap et als report researchers of this study decided to evaluate the clinical outcome of eculizumab among subsequent CHAPLE patients who are placed on this therapy In parallel molecular investigations on biological samples under eculizumab therapy are being carried to dissect the key alterations under complement C5 blockade
The current study is based on use of high-throughput methods to investigate PILs including exome sequencing for the non-CHAPLE PILs transcriptomics proteome and microbiome investigations The aims of the study include 1 Discovery of signatures and biomarkers in CHAPLE 2 Identification of the molecular etiology of non-CHAPLE PILs and potentially discover novel gene defects The integrated application of genomics transcriptome proteomics and microbiome aims to identify key mediators and pathways operative in the pathogenesis of intestinal lymphangiectasias Serial evaluation and longitudinal follow up of patient samples under eculizumab anti-complement C5 antibody therapy investigates dynamic alterations in the pathological profiles in CHAPLE syndrome It is anticipiated that these studies will improve the diagnosis and treatment of CHAPLE and related conditions
Goals of the current study include
1 To discover novel gene defects underlying PILs not related to CD55 deficiency
2 To identify signatures of CHAPLE disease and non-CHAPLE PILs that may reveal key mediators of disease and additional novel therapeutic targets
3 To explore the efficacy of eculizumab in a larger group of CHAPLE patients from unrelated families with variable degree of disease severity
4 To analyze patient samples collected before and during eculizumab therapy with the following objectives
1 To understand relations between eculizumab concentration complement function CH50 AH50 and complement protein levels C3 C5 CFB C3a C5a sC5b-9 Bb Ba
2 To explore biomarkers of inflammation and thrombosis complications of the disease that can occur in certain affected individuals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
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 |
|---|---|---|---|
| ZIAAI000717-22 | NIH | None | httpsreporternihgovquickSearchZIAAI000717-22 |