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 • National Institutes of Health NIH
Publication Number
US-9804171-B2
Publication Date
2017-10-31
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). The method utilizes a panel of at least five clinical analyses or tests on serum samples to determine the risk of PANS and/or PANDAS. The tests include enzyme linked immunosorbent assays (ELISAs) measuring antibody titers against specific neuronal antigens such as lysoganglioside, tubulin, dopamine receptors D1 and D2, serotonin receptors 5HT2A and 5HT2C, as well as a final assay quantifying calcium/calmodulin-dependent protein kinase activity using a neuronal cell line. The results from these assays are combined using an algorithm to assess the likelihood of a PANS or PANDAS diagnosis.
The problem solved by the invention is the lack of reliable clinical methods or tests to confirm a diagnosis of PANS and/or PANDAS, which has made timely and effective treatment challenging. Existing diagnostic criteria for PANDAS and PANS rely on observational clinical features and are insufficient for confidently diagnosing these disorders, leading to underdiagnosis and delayed or inappropriate therapy. This lack of diagnostic tools also hinders acceptance and coverage of treatment options, including antibiotic therapy, anti-inflammatory agents, intravenous immunoglobulin, and plasmapheresis.
The invention addresses this unmet need by providing a laboratory-based panel that objectively measures autoimmune responses to neuronal antigens and functional signaling effects, thus enabling clinicians to more accurately and rapidly diagnose PANS or PANDAS. This is expected to improve patient outcomes by facilitating earlier and more appropriate therapeutic interventions. The method is especially directed to PANDAS, a subset of PANS, but is also applicable to related neuropsychiatric disorders with similar autoimmune characteristics.
Claims Coverage
The patent includes multiple independent claims focused on methods of analyzing patient samples to detect antibodies against neuronal antigens and to measure kinase activity, providing the basis for diagnosing PANS/PANDAS.
Simultaneous antibody titers measurement against four neuronal antigens
A method comprising providing a surface with lysoganglioside, tubulin, dopamine receptor D1, and dopamine receptor D2 immobilized thereon, contacting the surface with a patient sample to form specific antibody/antigen complexes, and measuring antibody titers for each antibody against these antigens.
Functional assay measuring calcium/calmodulin-dependent protein kinase II activity
Including an assay for measuring CaM Kinase II activity performed by contacting the patient sample with the assay and measuring the resulting enzyme activity.
Combination of ELISA-based antibody detection with CaM Kinase II functional assay
A method that integrates measuring antibody titers against specified neuronal antigens with the measurement of calcium/calmodulin-dependent protein kinase II activity from the same patient sample.
Use of assay plates differentially coated with neuronal antigens for antibody detection
Methods include assay plates where separate portions are coated individually with lysoganglioside, tubulin, dopamine receptor D1, or dopamine receptor D2 for specific antibody titer measurements.
Application to various sample sources including serum and cerebrospinal fluid
Methods disclosed are applicable to samples from blood serum or cerebrospinal fluid to provide diagnostic information.
The claims cover a diagnostic method combining multiple antibody titer assays against neuronal antigens with a functional kinase activity assay to determine the likelihood of PANS or PANDAS, thereby providing a reliable immunological diagnostic tool.
Stated Advantages
Allows clinicians to prescribe treatments more effectively and timely than was previously possible.
Provides a reliable direct clinical evidence for PANS/PANDAS diagnosis, overcoming difficulties with symptom-based diagnostic criteria.
Enables significant improvement in patient outcomes by facilitating accurate and early diagnosis.
Supports transition of treatments from experimental phases to gaining insurance coverage by providing objective diagnostic data.
Documented Applications
Diagnosis and risk assessment of pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infection (PANDAS).
Determining candidacy for treatments including antibiotic therapy, anti-inflammatory therapy, intravenous immunoglobulin therapy, and plasmapheresis therapy for patients suspected of having PANS or PANDAS.
Assessment of autoimmune neuropsychiatric disorders with symptoms such as obsessions, compulsions, tics, autistic-like behaviors, anorexia nervosa, and deterioration in handwriting among pediatric patients.
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