Transcriptome and Metabolic Analyses of CHAPLE Disease
关键词
抽象
描述
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.
日期
最后验证: | 07/31/2019 |
首次提交: | 05/11/2019 |
提交的预估入学人数: | 05/11/2019 |
首次发布: | 05/14/2019 |
上次提交的更新: | 08/12/2019 |
最近更新发布: | 08/13/2019 |
实际学习开始日期: | 06/14/2018 |
预计主要完成日期: | 09/14/2019 |
预计完成日期: | 06/14/2020 |
状况或疾病
干预/治疗
Drug: CHAPLE patients on eculizumab
相
手臂组
臂 | 干预/治疗 |
---|---|
CHAPLE patients, without eculizumab treatment Patients with suspected CHAPLE syndrome undergo flow-cytometry based CD55 surface staining of peripheral blood samples. Those patients with loss of CD55 protein expression are diagnosed with CHAPLE syndrome. A subgroup of the CHAPLE patients describe only mild symptoms and are not treated with eculizumab, but monitored closely for any disease progression. | |
Control subjects- no intervention Healthy subjects with no history of any chronic disease. All investigational analyses are performed on both the case and the control subjects. Therefore, the same type of biological specimens collected from the case group are collected from the control group simultaneously. | |
Non-CHAPLE PILs PIL patients with intact CD55 on flow-cytometry assesment undergo genetic testing to exclude a potential missense mutation in the CD55 gene that impairs its function while retaining protein expression. Overall, patients and their parents undergo exome sequencing as trios, and examined for potential gene mutations underlying their disease. Non-CHAPLE PILs are also examined by high-throughput investigation similarly to CHAPLE patients. | |
CHAPLE patients on eculizumab Among CHAPLE patients, there is a subgroup who receive eculizumab treatment. These patients are prospectively followed and biological samples collected at baseline as well as periodically under therapy. Eculizumab (Soliris) is being provided for CHAPLE patients on an off-label basis upon approval of the physician's request of the drug by Turkish Medicines and Medical Devices Agency (TMMDA) of Turkish Ministry of Health. The dosage and interval of the drug is determined according to manufacturer's recommendations based on the weight of the patients. | Drug: CHAPLE patients on eculizumab Patients receive eculizumab as deemed necessary by the primary physician |
资格标准
有资格学习的性别 | All |
取样方式 | Non-Probability Sample |
接受健康志愿者 | 是 |
标准 | Inclusion Criteria: 1. Patients diagnosed with PIL form the study groups and deem eligible for the study unless there is a risk associated with blood draw. 2. The patients with CHAPLE syndrome who receive eculizumab therapy and consent to participate in this study are followed prospectively and clinical data collected. Biological sample collection and molecular investigations are to be made only if the patient is willing to provide biological samples, including peripheral blood and stool. Exclusion Criteria: 1. Presence of a concomitant disease that leads to hypoproteinemia at the time of starting eculizumab such as a urinary protein loss or a hepatic disease that affects production of proteins by liver. 2. A concomitant disease that leads to secondary intestinal lymphangiectasia such as a fontan procedure for congenital heart disease. 3. Unstable clinical condition not allowing blood draw, such as severe anemia. |
结果
主要结果指标
1. Reversal of protein-losing enteropathy [3-6 months]
2. Reversal of patient-specific major symptoms [12-18 months]
次要成果指标
1. Reversal of other systemic components of the disease. [12-18 months]
2. Correction of previous biochemical and radiological abnormalities [6-18 months]
3. Cessation of previous medications [3-18 months]