Measuring success: utility of biomarkers in sickle cell disease clinical trials and care

Abstract

Progress in the care of sickle cell disease (SCD) has been hampered by the extreme complexity of the SCD phenotype despite its monogenic inheritance. While epidemiological studies have identified clinical biomarkers of disease severity, with a few exceptions, these have not been routinely incorporated in clinical care algorithms. Furthermore, existing biomarkers have been poorly apt at providing objective parameters to diagnose sickle cell crisis, the hallmark, acute complication of SCD. The repercussions of these diagnostic limitations are reflected in suboptimal care and scarcity of adequate outcome measures for clinical research. Recent progress in molecular and imaging diagnostics has heralded a new era of personalized medicine in SCD. Precision medicine strategies are particularly timely, since molecular therapeutics are finally on the horizon. This chapter will summarize the existing evidence and promising data on biomarkers for clinical care and research in SCD.

Integrin VLA-4 as a PET imaging biomarker of hyper-adhesion in transgenic sickle mice

“…The discovery of new biomarkers of VOEs to identify patients at risk for specific complications and to monitor treatment responses is a research priority. 42 There remains a paucity of objective findings to diagnose VOEs, which has hampered research and clinical care in SCD. 42,43 In particular, imaging studies of VOEs in humans have been restricted to single-photon emission computerized tomography or magnetic resonance imaging scans of bone marrow infarction, [44][45][46] a late event that does not always develop during VOEs.…”

High-throughput assessment of hemoglobin polymer in single red blood cells from sickle cell patients under controlled oxygen tension

“…Sickle cell disease has a variable clinical course for patients, with some having very severe outcomes and some having more benign (1). Despite decades of research, we have limited understanding of the reasons for this variability, and efforts to find useful genotypic or clinical predictors of benign prognosis have been unsuccessful, leaving us with no useful in vitro biomarkers (2). Fetal hemoglobin (HbF) can inhibit polymer formation, and experience with patients with genetic variants and patients who respond to hydroxyurea treatment by up-regulating fetal hemoglobin shows that patient outcomes can be improved by reducing the amount of hemoglobin polymer that will form in individual RBCs at a given oxygen tension (3)(4)(5)(6).…”

“…We are therefore unable to optimize delivery of a particular therapy, and we have no accurate way to compare and prioritize these experimental treatments. Most importantly, we are left to manage patients with crude and imprecise biomarkers (2).…”

5‐(Hydroxymethyl)furfural restores low‐oxygen rheology of sickle trait blood in vitro

“…This experimental system has previously been used to investigate SCD pathophysiology, including rheological mechanisms of vaso‐occlusion (Higgins et al , ; Higgins et al , ; Lu et al , ; Lu et al , ), correlations of in vitro and in vivo phenotypes (Wood et al , ), and the use of in vitro SCT phenotypes as a treatment target for SCD (Lu et al , ). There are currently no good in vitro biomarkers for the management of SCD (Kalpatthi & Novelli, ), and the need for their development has increased dramatically recently with the advent of experimental therapies for SCD whose optimization and comparative assessment crucially depends on the availability of validated in vitro markers (Benz et al , ).…”