Diagnostic method for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococci infection (PANDAS)
Inventors
Cunningham, Phina Madeleine • Shimasaki, Craig David • Swedo, Susan E. • Kirvan, Christine
Assignees
Moleculera Labs Inc • University of Oklahoma • US Department of Health and Human Services
Publication Number
US-10228376-B2
Publication Date
2019-03-12
Expiration Date
2034-03-13
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Abstract
The present invention provides a panel of at least five clinical analyses or tests (using serum samples) to determine the risk of pediatric acute-onset neuropsychiatric syndrome (PANS) and/or pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS) in an individual. These include enzyme linked immunosorbent assays (ELISAs) to measure antibody titers against neuronal antigens present in the brain; the neuronal antigens include lysoganglioside, tubulin, dopamine receptor D1, dopamine receptor D2, serotonin receptor 5HT2A, and serotonin receptor 5HT2C. Antibody titers against at least four of these neuronal antigens are required in the present methods; preferably antibody tiers against all of these neuronal antigens are measured. A final assay is used to quantify calcium/calmodulin-dependent protein kinase activity using a neuronal cell line. The results of these analyses or tests are then combined using an algorithm to determine whether a PANS or PANDAS diagnosis is appropriate for the individual. Depending on the diagnosis, an appropriate treatment can be determined.
Core Innovation
The invention provides a convenient and accurate diagnostic method for pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS). It involves a panel of at least five clinical tests using serum samples to determine the risk of PANS and/or PANDAS in an individual. The method includes enzyme linked immunosorbent assays (ELISAs) measuring antibody titers against specific neuronal antigens in the brain and a final assay quantifying calcium/calmodulin-dependent protein kinase activity in a neuronal cell line. The test results are combined using an algorithm to determine the likelihood of a PANS or PANDAS diagnosis, which informs treatment decisions.
The problem addressed is the lack of reliable clinical methods or tests to provide or confirm a diagnosis of PANS or PANDAS. Current diagnosis relies solely on observational clinical criteria, which makes it difficult for physicians to confidently diagnose and treat children with these disorders. The absence of diagnostic tools causes delays or reluctance in prescribing therapies, including antibiotic and immune modulation treatments, many of which may be aggressive or experimental. The invention aims to fill this unmet need by providing direct clinical evidence through multiple assays for the autoimmune basis of these neuropsychiatric disorders, enabling earlier and more effective treatment.
The invention emphasizes the importance of multiple assays, at least four ELISAs targeting antibodies against lysoganglioside, tubulin, dopamine receptor D1, dopamine receptor D2, and optionally serotonin receptors 5HT2A and 5HT2C, alongside a calcium/calmodulin-dependent protein kinase activity assay. The combined data increase the accuracy of PANS/PANDAS diagnosis compared to relying on symptoms or single tests. The methods include defined thresholds relative to normal controls to interpret assay results. The use of this multi-assay panel is designed to improve physician confidence, facilitate timely diagnoses, and contribute to transitioning treatment approaches out of experimental status, potentially leading to broader insurance coverage and better patient outcomes.
Claims Coverage
The claims cover a diagnostic method involving multiple assays to analyze patient samples for antibodies against neuronal antigens and measuring kinase activity. There are multiple independent claims describing methods involving immobilized neuronal antigens, measuring antibody titers, and assessing CaM Kinase II activity.
Multiplex assay of antibody titers against neuronal antigens
Providing a surface or assay plate with at least four immobilized molecules selected from lysoganglioside (including lysoganglioside GM1), tubulin, dopamine receptor D1, dopamine receptor D2, human serotonin receptor 5HT2A, and human serotonin receptor 5HT2C. Contacting the surface with a patient sample to form antibody/molecule complexes and measuring antibody titers against at least four corresponding antibodies.
Measurement of calcium/calmodulin-dependent protein kinase II (CaM Kinase II) activity
Providing and contacting an assay for measuring CaM Kinase II activity with the patient sample and measuring the CaM Kinase II activity as part of the diagnostic process.
Use of serum or cerebrospinal fluid as sample
Using serum obtained from blood or cerebrospinal fluid as the patient sample for detecting antibodies and measuring kinase activity.
Implementation on microtiter or assay plates
Employing one or more assay plates, including microtiter plates, each separately comprising individual neuronal antigens to perform the antibody titer assays separately on different portions of the patient sample.
The claims collectively define a diagnostic method combining multiplex antibody titer analysis against selected neuronal antigens with a functional assay measuring calcium/calmodulin-dependent protein kinase II activity in patient serum or cerebrospinal fluid. This provides a reliable method to assess the likelihood of PANS or PANDAS.
Stated Advantages
Allows treating clinicians to prescribe treatments in a more effective and timely manner due to reliable diagnosis.
Expected to significantly improve patient outcomes with PANS and/or PANDAS.
Provides direct clinical evidence to support diagnosis, overcoming physician reluctance and aiding early identification.
Supports moving treatments out of experimental phase toward insurance coverage by increasing diagnostic accuracy.
Combining multiple assays enhances the accuracy of diagnosis compared to current observational criteria alone.
Documented Applications
Diagnosis of pediatric acute-onset neuropsychiatric syndrome (PANS).
Diagnosis of pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).
Diagnosis of similar autoimmune-based neuropsychiatric diseases, including autistic-like behaviors and anorexia nervosa.
Determination of appropriate treatment options such as antibiotic therapy, anti-inflammatory therapy, intravenous immunoglobulin therapy, and plasmapheresis therapy based on diagnostic results.
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