Broadly effective metabolic and immune recovery with C5 inhibition in CHAPLE disease

Area of Science:

• Immunology
• Gastroenterology
• Genetics

Background:

• CHAPLE disease results from CD55 deficiency, causing complement system overactivation, immune dysregulation, and protein loss.
• This leads to severe gastrointestinal pathology, angiopathic thrombosis, and immunodeficiency.
• Current treatments are limited, highlighting the need for effective therapeutic strategies.

Purpose of the Study:

• To evaluate the efficacy of eculizumab, a complement C5 inhibitor, in treating patients with CHAPLE disease.
• To assess the impact of C5 blockade on clinical manifestations, immune function, and metabolic parameters.
• To demonstrate the potential of targeting the complement system for managing CD55 deficiency.

Main Methods:

• In vivo human data collection from patients with CHAPLE disease undergoing eculizumab treatment.
• Aptamer-based proteomic profiling for serum protein concentration analysis.
• Assessment of gastrointestinal pathology, immune status, microbiome composition, and growth parameters.

Main Results:

• Eculizumab treatment led to the cessation of gastrointestinal pathology.
• Patients showed restoration of normal immunity and metabolism, with rapid normalization of immunoglobulin and other serum proteins.
• A healthy gut microbiome was re-established, and patients exhibited catch-up growth, discontinuing prior treatments.

Conclusions:

• Blockade of complement C5 by eculizumab effectively regulates the innate immune complement system in humans with CD55 deficiency.
• Eculizumab substantially reduces the pathophysiological manifestations of CHAPLE disease.
• This study establishes eculizumab as a promising therapeutic option for managing this lethal genetic disorder.