Emerging disease-modifying therapies for sickle cell disease

Abstract

Sickle cell disease afflicts millions of people worldwide and approximately 100,000 Americans. Complications are myriad and arise as a result of complex pathological pathways ‘downstream’ to a point mutation in DNA, and include red blood cell membrane damage, inflammation, chronic hemolytic anemia with episodic vaso-occlusion, ischemia and pain, and ultimately risk of cumulative organ damage with reduced lifespan of affected individuals. The National Heart, Lung, and Blood Institute’s 2014 evidence-based guideline for sickle cell disease management states that additional research is needed before investigational curative therapies will be widely available to most patients with sickle cell disease. To date, sickle cell disease has been cured by hematopoietic stem cell transplantation in approximately 1,000 people, most of whom were children, and significantly ameliorated by gene therapy in a handful of subjects who have only limited follow-up thus far. During a timespan in which over 20 agents were approved for the treatment of cystic fibrosis by the Food and Drug Administration, similar approval was granted for only two drugs for sickle cell disease (hydroxyurea and L-glutamine) despite the higher prevalence of sickle cell disease. This trajectory appears to be changing, as the lack of multimodal agent therapy in sickle cell disease has spurred engagement among many in academia and industry who, in the last decade, have developed new drugs poised to prevent complications and alleviate suffering. Identified therapeutic strategies include fetal hemoglobin induction, inhibition of intracellular HbS polymerization, inhibition of oxidant stress and inflammation, and perturbation of the activation of the endothelium and other blood components (e.g. platelets, white blood cells, coagulation proteins) involved in the pathophysiology of sickle cell disease. In this article, we present a crash-course review of disease-modifying approaches (minus hematopoietic stem cell transplant and gene therapy) for patients with sickle cell disease currently, or recently, tested in clinical trials in the era following approval of hydroxyurea.

Sickle cell disease: Progress made & challenges ahead

“…Several other pharmacological agents targeting specific sites in the pathophysiologic pathway of SCD are in the pipeline as drug developers take the advantage of orphan drug designation policies now existing in many countries. Several emerging drugs are being studied both alone and in combination with hydroxyurea, as combination therapies offer the best prospects for optimizing disease outcomes 19 .…”

Beneficial Effects of Soluble Guanylyl Cyclase Stimulation and Activation in Sickle Cell Disease Are Amplified by Hydroxyurea: In Vitro and In Vivo Studies

“…Sickle cell anemia is now recognized as a global health problem (Kato et al, 2018) and while curative therapy for SCA exists in the form of hematopoietic stem cell transplantation, its availability is very restricted (Yawn et al, 2014). Despite concerted efforts by researchers and the pharmaceutical industry to develop novel drugs for the treatment of SCA (Telen, 2016;Conran and Torres, 2019), only three substances have been FDA approved for SCA therapy since hydroxyurea's approval over 20 years ago, and it is probable that multi-drug approaches, possibly still involving the use of hydroxyurea, will evolve for the management of the disease (Carden and Little, 2019).…”

Convergence of Inflammatory Pathways in Allergic Asthma and Sickle Cell Disease

“…Inhaled corticosteroids have been proposed to be used to prevent additional episodes of vaso-occlusive crisis in pediatric patients, and recent studies have underscored the feasibility of this approach in young children (47). Inhaled steroids given to nonasthmatic patients with SCD have demonstrated considerable promise, with significant reductions in pain and sVCAM levels as well as inflammatory macrophage markers, underscoring the potential for targeting inflammation to improve health outcomes in these patients (48)(49)(50). Whether treatments for specific asthma endotypes can be extended to patients with SCD remains unclear, though given the underlying differences in inflammation tailored therapeutic strategies may be required.…”