MyoSyntax Corporation — Department of Health and Human Services SBIR Phase I: NHLBI

Description

PROJECT SUMMARY Sickle cell disease is a major clinical problem in the US France the United Kingdom Brazil and in Africa India and the Middle East A recent study shows that the annual cost of medical care in the US for people who suffer from sickle cell disease exceeds $ billion Sickle hemoglobin HbS polymerization drives the pathophysiology of this disease Fetal hemoglobin HbF is present throughout fetal development and is replaced by adult hemoglobin HbA A major therapeutic goal in sickle cell disease is to induce high HbF levels in sickle erythrocytes We contend that the amount of HbF per F cell HbF F cell and the distribution of concentrations of HbF F cells is a critical determinant of disease severity Existing measurement of hemolysate HbF concentration or the number of F cells in blood does not measure HbF F cell or the distribution of HbF F cell in a patient blood sample This unmet need is critical because even patients with high HbF can have severe disease since their HbF is unevenly distributed among F cells and many F cells have insufficient HbF concentrations to inhibit HbS polymerization We hypothesize that the proportion of F cells that have enough HbF to thwart HbS polymerization is the most critical predictor of the likelihood of severe sickle cell disease HbF F cell should be the phenotype studied in HbF induction therapeutics and would also be useful in developing risk scores that project likelihoods for disease severity A clinical method for rapidly ascertaining HbF F cell is currently not available As HbF concentrations among F cells are highly variable and clinically relevant the predictive value of HbF would be improved with an assay measuring the distribution of HbF concentrations within F cells Physicians would be able to provide better care using an HbF diagnostic as a standard method to assess which patients have higher risk as well those patients with lower risk Analysis of sickle cell donors resulted in statistically significant associations between HU treatment efficacy and F cell frequency but did not confirm other risk associations We expect to use a Bayesian classifier to associate different distributions of concentration of HbF F cell to patient clinical data and overall severity AIM Develop a gold standard method to validate an HbF F cell diagnostic In this aim we will develop and optimize the absolute quantitation of HbF by HPLC to provide a gold standard validation of MyoSyntax s HbF F cell diagnostic which can determine the risk of sickle cell disease crisis Absolute determination of HbF pg cell via HPLC will be completed to precisely and absolutely correlate F cell MFI to HbF quantity This method will be used to qualify microsphere calibrators according to an FDA approved clinical standard AIM Evaluate diagnostic performance in the prediction of sickle cell crisis risk in humans We will evaluate the assay performance in terms of specificity and sensitivity with a spectrum of total HbF levels and disease phenotypes to determine distributions of HbF F cell and their association with disease severity among sickle cell individuals The prognostic performance of HbF F cell will be contrasted to the current clinical diagnostic standard total HbF content expressed as a percent mean This will provide the preliminary data we believe would justify a Phase II SBIR application The long term goal is to develop a test for HbF F cell profiling and a license for use of an online tool for disease risk determination that can be done in any hospital with flow cytometry and internet capability NARRATIVE In this study we seek to validate a quantitative fetal hemoglobin HbF diagnostic across sickle cell adult subjects using multi level HbF coated calibrator beads and quantitative HPLC We seek to validate the concentration or distribution of fetal hemoglobin in which elicits a protective effect