Transcriptome and Metabolic Analyses of CHAPLE Disease


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Özen A. O. (Executive) , Barış S. , Aydıner E. , Lenardo M. J.

Project Supported by Public Organizations in Other Countries, 2019 - 2024

  • Project Type: Project Supported by Public Organizations in Other Countries
  • Begin Date: August 2019
  • End Date: August 2024

Project Abstract

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. Until recently, there has been no curative therapy for CHAPLE patients. The Parties have shown that the disease 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 these scientific observations, the Parties were able to develop a targeted therapy for this deadly disease using an antibody called eculizumab, which blocks the complement protein C5. The current study aims to further dissect the molecular alterations underlying CHAPLE and CHAPLE-like diseases, identify key molecules that lead to protein-losing enteropathy and discover biomarkers that can guide therapy. The Parties anticipate that the current studies will improve the diagnosis and treatment of these disorders.  

 

 

II.   Goal(s) of Project

 

#1. To analyze pre-existing and future samples collected before and during eculizumab therapy to:

 

a.  identify signatures of CHAPLE disease that may reveal key mediators of disease and additional novel   therapeutic targets.

b.  understand relations between eculizumab concentration, complement function (CH50, AH50) and   complement protein levels (C3, C5, CFB, C3a, C5a, sC5b-9, Bb, Ba)

c.  explore biomarkers of inflammation and thrombosis, complications of the disease that can occur in certain affected individuals.

 

#2.  To study non-CHAPLE PLEs for underlying gene defects, which may potentially bring novel   therapies for this group of patients, similar to a process in CHAPLE disease.