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NIH researchers find genetic cause, possible treatment for CHAPLE disease
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Investigators from the National Institute of Allergy and Infectious Diseases, part of the NIH, have identified a genetic cause and possible treatment strategy for CHAPLE disease, a rare and potentially fatal autoimmune disorder.
CHAPLE disease (CD55 deficiency with hyperactivation of complement, angiopathic thrombosis, and protein-losing enteropathy) is a form of primary intestinal lymphangiectasia also known as Waldmann’s disease, which researchers first described in the 1960s. Disease characteristics include primary intestinal lymphangiectasia, bowel inflammation, and thrombotic events, and there are no treatments currently available.
“People with CHAPLE disease lack CD55 protein and, with it, the ability to control complement activity,” Michael J. Lenardo, MD, chief of the Molecular Development of the Immune System Section of NIAID’s Laboratory of Immunology, said in a press release. “The question is whether treating people with a substitute for CD55’s activity can help slow or reverse the symptoms of this disease.”
First the researchers performed genetic sequencing in 11 children with the disease and their family members, and found two copies of a defective CD55 gene in each child. This prevented expression of the CD55 protein, which contributes to immune regulation by inhibiting complement activation.
In the study manuscript, Lenardo and colleagues described complement as “a system of interacting proteins that provides host defense by destroying microbes and modulating immunity with soluble anaphylatoxins governed by multiple regulators, including CD55.”
While complement can help fight infections, it can also damage body tissue, and the investigators found that in CHAPLE disease, the lack of CD55 protein resulted in uninhibited complement, which then damaged blood and lymph vessels in the lower GI tract and led to the loss of protective immune proteins and blood cells. This caused symptoms like abdominal pain, bloody diarrhea, vomiting, malabsorption, delayed growth, swelling in the legs, recurrent lung infections and blood clots in patients.
Having observed that hyperactivity of complement drives these severe symptoms, the investigators then evaluated drugs approved by the FDA for other diseases in patient immune cell samples to determine if they could stop this process.
They found that Soliris (eculizumab, Alexion), a humanized monoclonal antibody approved for paroxysmal nocturnal hemoglobinuria, decreased the production of complement in exposed immune cells. NIAID and other study collaborators plan to further evaluate this drug as a potential first treatment for patients with CHAPLE disease, according to the press release.
The investigators noted in the manuscript that a simultaneously published study by Kurolap et al. “shows that eculizumab therapy in a family with the CHAPLE syndrome resulted in attenuated protein-losing enteropathy and reduced bowel-movement frequency within 100 days after the initiation of therapy.”
“These findings are an example of how increasingly sophisticated techniques in genetics research inform our understanding of the immune system — especially our understanding of rare, inherited immune diseases,” Anthony S. Fauci, MD, NIAID Director, said in the press release. – by Adam Leitenberger
Disclosures: The researchers report no relevant financial disclosures.
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