Protein-Losing Enteropathies Clinical Trial
Official title:
Transcriptome and Metabolic Analyses of CHAPLE Disease Patients With or Without Eculizumab Treatment
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 options.The 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.
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 al.'s 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.
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