Accelerating the Science of SCD Therapies—Is a Cure Possible?

Abstract

Nearly 7 decades have passed since seminal studies of hemoglobin led to the characterization of sickle cell anemia as the first defined molecular disease. These foundational insights into sickle cell disease (SCD) initiated an exciting era of medicine that has substantially expanded the understanding of the molecular basis of thousands of disorders over the ensuing years. The field of molecular medicine is now at a pivotal moment in its history, a time when scientific capabilities to read, edit, and reprogram the human genetic code for therapeutic approaches are within reach. The rapid pace of innovation in emerging technologies of gene editing and translational research suggest that it is time to accelerate curative therapies for the first defined molecular disease.More than 100 years have passed since Archives of Internal Medicine (now JAMA Internal Medicine) published Herrick's description of misshapen red cells in a Grenadan medical student. 1 In hindsight, it is now understood how this"puzzling"clinicalobservationinanindividualofAfrican ancestry fits within the current "central dogma" of molecular medicine: DNA-RNA-protein-disease. Sickle cell disease is a hemolytic anemia caused by a mutation in the β globin subunit of adult hemoglobin (HbA) that substitutes valine for glutamic acid at position 6. When deoxygenated, HbS polymerizes, rendering the red cell rigid, viscous, and abnormallyadherenttothecapillaryendothelium.Thisimpedes blood flow in the microcirculation, causing ischemia and microinfarcts that lead to painful crises, strokes, renal failure, retinopathy, and myriad end-organ injuries.Although the discovery of the molecular basis of SCD was a triumphant milestone in molecular medicine, 2 it is still a tragic truth that in the absence of access to treatments, infants born with SCD are unlikely to live to adulthood in many parts of the world. Over the past 4 decades, advances such as penicillin prophylaxis, standardized vaccine schedules, transfusion support, and hydroxyurea therapy have significantly extended life expectancy for those with SCD. Nevertheless, many individuals with SCD in the United States still lack a patientcentered medical home with access to evidence-based care that optimizes health outcomes.Within the current therapeutic armamentarium, hydroxyurea is the first successful treatment strategy to address the molecular basis of SCD through the induction of a partial increase in the production of fetal hemoglobin (HbF). Fetal hemoglobin does not sickle and offers the added benefit of inhibiting deoxygenated-HbS polymerization. Approved by the US Food and Drug Administration (FDA) in the late 1980s, hydroxyurea prolongs patient survival and reduces painful crises and acute chest syndrome. Challenges and adverse effects

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 , ).…”

Motivations and Decision-Making of Adult Sickle Cell Patients in High-Risk Clinical Research

“…Complicating the risk-benefit assessment is that transplantation or gene therapy technically offers the hope of a cure for SCD [25,26] unlike many clinical trials, including most cancer trials. Although the consent forms for these clinical trials stress that these are research interventions aiming to make transplantation and gene therapy safer and more effective, they also recognize that the participants' SCD could be cured while explicitly cautioning "this cannot be guaranteed and your disease may return."…”

The molecular basis for the prothrombotic state in sickle cell disease

“…In addition, curing SCD either through stem cell transplantation or gene therapy has become a reality for a small number of patients. 2 Given the October 2019 joint National Institutes of Health (NIH)-Bill and Melinda Gates Foundation funding declaration, inclusion of patients from high disease burden resource-scarce settings in such trials of novel curative therapies seems plausible. 3 Prospects appear particularly promising for SCD patients in resource-scarce settings worldwide, where the need is greatest.…”