Methods of diagnosing and treating CD55 deficiency, hyperactivation of complement, angiopathic thrombosis and protein losing enteropathy (CHAPLE), a newly identified orphan disease
Inventors
Lenardo, Michael J. • Su, Helen • Ozen, Ahmet Oguzhan • Comrie, William Andrew • Boztug, Kaan • Ardy, Rico Chandra
Assignees
US Department of Health and Human Services
Publication Number
US-12168802-B2
Publication Date
2024-12-17
Expiration Date
2037-09-13
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Abstract
Disclosed herein are methods of diagnosing, and treating and/or preventing CD55-deficiency, hyperactivation of complement, angiopathic thrombosis and protein-losing enteropathy (CHAPLE). The method of diagnosing includes: providing a sample from a patient; performing an assay detecting at least one of at least one mutation in a DNA sequence of a CD55 gene, at least one mutation in a RNA sequence of a CD55 transcript, at least one mutation in a DNA sequence of a CD55 complementary-DNA (cDNA), CD55 protein, CD55 protein binding, complement deposition or combination thereof, and diagnosing the patient with CHAPLE. The method of treating and/or preventing at least one symptom of CHAPLE includes: administering an effective amount of a composition comprising at least one complement inhibitor to a subject in need thereof, wherein the composition is effective in treating or preventing at least on symptom of CHAPLE. The disclosure further relates to compositions effective at treating and/or preventing CHAPLE.
Core Innovation
The invention disclosed relates to methods of diagnosing, treating, and preventing CD55 deficiency, hyperactivation of complement, angiopathic thrombosis and protein-losing enteropathy (CHAPLE), a newly identified orphan disease. The methods encompass providing a patient sample and detecting mutations in the DNA, RNA, or cDNA sequences of the CD55 gene or transcript, detecting CD55 protein levels or function, complement deposition, or a combination thereof to diagnose CHAPLE. Treatment involves administering an effective amount of a composition containing at least one complement inhibitor to a subject in need, which is effective in treating or preventing one or more symptoms of CHAPLE.
The problem addressed stems from the difficulty in diagnosing and treating rare orphan diseases like CHAPLE, which is characterized by protein-losing enteropathy, hypoproteinemia, edema, and thrombotic events, among other symptoms. Existing knowledge indicated that CD55 deficiency on red blood cells is rare and poorly characterized as a disease, and an accurate diagnosis of such rare diseases often takes years due to symptom overlap with more common diseases.
This invention solves the problem by identifying specific homozygous loss-of-function mutations in the CD55 gene that cause near complete loss or dysfunction of CD55 protein leading to CHAPLE syndrome, and provides assays to accurately detect these mutations and protein deficiencies. Furthermore, it provides therapeutic compositions comprising complement inhibitors such as therapeutic antibodies, serine protease inhibitors, soluble complement regulators, complement component inhibitors, and anaphylatoxin receptor antagonists to effectively treat or prevent CHAPLE symptoms.
Claims Coverage
The independent claims cover methods of treating CD55 deficiency, hyperactivation of complement, angiopathic thrombosis and protein losing enteropathy (CHAPLE) by administering specific therapeutic antibodies.
Method of treating CHAPLE by administering therapeutic antibodies
A method of treating a subject diagnosed with CHAPLE comprising administering an effective amount of a composition comprising at least one therapeutic antibody selected from eculizumab, ALXN1007, neutrazumab, Pexelizumab, ofatumumab, HuMax-CD38, TNX-558, TNX-234, or TA106 to the subject.
The claims focus on therapeutic methods involving administration of specific complement-inhibiting antibodies to treat CHAPLE, specifically naming various antibodies with eculizumab receiving particular emphasis.
Stated Advantages
The therapeutic compositions are effective in treating or preventing at least one symptom of CHAPLE disease.
Complement inhibition effectively controls dysregulated complement activation, inflammatory cytokine production, and thrombotic complications associated with CD55 deficiency.
Early and accurate diagnosis using the described assays can lead to targeted therapy, improving patient prognosis for this rare disease.
Documented Applications
Diagnosis of CHAPLE by detecting mutations in CD55 gene sequences or protein deficiencies in patients exhibiting related symptoms.
Treatment and prevention of CHAPLE symptoms by administering complement inhibitors, including therapeutic antibodies, serine protease inhibitors, soluble complement regulators, complement component inhibitors, or anaphylatoxin receptor antagonists.
Use of complement inhibitors such as eculizumab and compstatin to inhibit complement activation and manage complement-mediated pathology in CHAPLE patients.
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