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Disease-modifying therapies for SCD
which makes the sickle RBC fragile, less deformable, and dehydrated, and subsequently more susceptible to endothelial adhesion through activation of adhesion receptors.4-7 Downstream consequences include microvas- cular occlusion, leukocyte and platelet activation, and a pathologically altered endothelium all existing in a pro- inflammatory and pro-thrombophilic plasma milieu.8-13 The biomechanical properties of sickle RBC are depend- ent on intrinsic factors, such as the composition of the hemoglobin [e.g., presence of the anti-sickling fetal hemo- globin (HbF: a2γ2)], membrane integrity, cellular volume and hydration, cytosolic make-up, and extrinsic factors, such as inflammatory cytokines, activated endothelium, and other blood components including platelets, leuko- cytes, and proteins involved in coagulation.8 Clinical man- ifestations of the presence of HbS polymerization are wide-ranging and include chronic hemolytic anemia, episodic microcirculatory vaso-occlusion with tissue ischemia and pain, and ultimately chronic end-organ dam- age that can reduce the lifespan of an individual with SCD.14
Due to its impact on morbidity and mortality, SCD is increasingly being recognized as a global health problem. Researchers in academia and industry have reinvigorated efforts to cure patients with SCD; and where that is not possible because of medical and socioeconomic barriers they aim to prevent, delay, and mitigate its protean com- plications.15-17 Curing SCD through stem cell transplanta- tion and achieving durable responses through gene thera- py have become realities for some patients.18,19 However, as stated by the 2014 evidence-based guidelines from the National Heart, Lung, and Blood Institute (NHLBI), addi- tional research is needed before potentially curative thera- pies are widely, safely, and inexpensively available to most patients.20 Therefore, in the era following approval of hydroxyurea by the United States Food and Drug Administration (FDA), providers will need to rely on improving patients’ outcomes through utilization of one or more additional emerging novel therapies and advances
in care. Although the economic cost benefit of such an approach is difficult to predict, conceptually this may evolve into a multi-faceted approach to SCD that is similar to that seen with multi-agent chemotherapy for the suc- cessful management of cancer.21
In this context, we present emerging non-genetic approaches (i.e. those that do not involve stem cell or gene therapy) currently or recently in clinical trials that offer innovative treatment and palliation in SCD. While we do include agents involved in epigenetic targeting, excellent reviews of other genetic approaches for disease modifica- tion or cure (i.e. those receiving stem cell transplants or gene therapy through gene addition, correction, or editing) can be found elsewhere.19,22,23
Methods
Relevant literature was identified through various mech- anisms, including using search terms ‘sickle cell disease’ and ‘novel treatments’ in MEDLINE, reviewing recent abstracts presented at the American Society of Hematology annual meetings, and examining recent, relevant reviews by others in the field.15-17,21,24-28 Trials actively recruiting pediatric or adult patients with SCD, and which included subjects aged 18 years or older, as of February 15, 2019 were also evalu- ated through ClinicalTrials.gov. Upon review of each result, we excluded those trials involving gene modifica- tion, including stem cell transplant, gene addition, correc- tion, or editing. As we outline in Online Supplementary Tables S1 and S2, we broke down what we thought were novel and important treatments into two groups - those characterized by targeting the abnormal HbS and damaged sickle RBC (i.e. intrinsic to the RBC, including formation of deoxy-HbS and its polymerization in a dehydrated sickle RBC) (Figure 1) and those targeting sequelae downstream from the red cell (i.e. extrinsic to the RBC, including abnor- mal endothelial and cellular adhesion, vascular tone, other blood components, and inflammation) (Figure 2).
Figure 1. Red cell intrinsic targets. The figure illustrates the therapeutic targets within the red cell precursor [DNA1, and the sickle red blood cell (RBC), HbS5, e.g. voxelator, and polymer formation16], which are most likely to modify sickle cell disease and to affect more than a single downstream sequelae (pain, inflammation, vasculopathy, so forth). RBC image: https://steemit.com/stemng/@gbindinazeez/sickle-cell-anaemia-an-endemic-disease-20181122t215228805z-post]
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