Using disease-modifying therapies in sickle cell disease.
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ABSTRACT:
SUBMITTER: Rai P
PROVIDER: S-EPMC10727073 | biostudies-literature | 2023 Dec
REPOSITORIES: biostudies-literature
Publications
Using disease-modifying therapies in sickle cell disease.
Rai Parul P Ataga Kenneth I KI
Hematology. American Society of Hematology. Education Program 20231201 1
As curative therapy using allogeneic hematopoietic stem cell transplantation as well as gene therapy and gene editing remains inaccessible to most patients with sickle cell disease, the availability of drug therapies that are safe, efficacious, and affordable is highly desirable. Increasing progress is being made in developing drug therapies based on our understanding of disease pathophysiology. Four drugs, hydroxyurea, L-glutamine, crizanlizumab, and voxelotor, are currently approved by the US ...[more]
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Project description: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.
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