New insights into the pathophysiology and development of novel therapies for sickle cell disease.
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ABSTRACT:
SUBMITTER: Moerdler S
PROVIDER: S-EPMC6245971 | biostudies-literature | 2018 Nov
REPOSITORIES: biostudies-literature
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Project description:Background: Sickle cell disease (SCD) is an inherited hemoglobinopathy associated with severe morbidity, impaired quality of life, and premature mortality. Hematopoietic stem cell transplantation (HSCT) is the only curative treatment available for patients with SCD and has a >90% event-free survival when a matched related donor is used. However, availability of human leukocyte antigen (HLA)-identical sibling donors for the SCD population is limited. The use of HLA-matched unrelated donors or related haploidentical donors has the potential to expand the donor pool. Methods: We reviewed the current literature on the indications for SCD transplantation, donor options, and the emerging use of gene therapy as a treatment option. Google Scholar and PubMed were searched using the terms SCD, bone marrow transplantation, donor sources, gene therapy, HSCT, and HLA matching. Additional articles were identified from the bibliographies of retrieved articles. All articles were reviewed for pertinent information related to SCD and transplantation. Results: HSCT has the potential to establish donor-derived normal erythropoiesis with stable long-term engraftment, amelioration of symptoms, and stabilization of organ damage. The majority of HSCT has been performed in children from HLA-identical sibling donors and has resulted in excellent rates of survival. The use of alternate donors such as HLA-matched unrelated donors and haploidentical donors has the potential to expand the applicability of HSCT for SCD. Early results in gene therapy for SCD are encouraging. Conclusion: Evaluation of the long-term benefits of curative therapies for SCD requires comparative clinical trials and studies of late effects.
| S-EPMC6584191 | biostudies-literature
Project description:Sickle cell disease has been very well characterized as a single amino acid molecular disorder of hemoglobin leading to its pathological polymerization, with resulting red cell rigidity that causes poor microvascular blood flow, with consequent tissue ischemia and infarction. More recently, an independent spectrum of pathophysiology of blood vessel function has been demonstrated, involving abnormal vascular tone and activated, adhesive endothelium. These vasculopathic abnormalities are attributable to pathways involving hemolysis-associated defects in nitric oxide bioavailability, oxidative stress, ischemia-reperfusion injury, hemostatic activation, leukocytes and platelets. Vasculopathy of sickle cell disease has been implicated in the development of pulmonary hypertension, stroke, leg ulceration and priapism, particularly associated with hemolytic severity, and reported also in other severe hemolytic disorders. This vasculopathy might also play a role in other chronic organ dysfunction in patients with sickle cell disease. These pathways present novel targets for pharmacologic intervention, and several clinical trials are already under way. The authors present their perspectives of a workshop held at the National Institutes of Health in August 2008 on vasculopathy in sickle cell disease, along with meritorious future scientific questions on the topic of vascular complications of sickle cell disease.
| S-EPMC3209715 | biostudies-literature
Project description:Introduction:Sickle cell disease (SCD) is an orphan disease in the United States, but is highly prevalent worldwide. Only two drugs, hydroxyurea and L-glutamine, are approved for this disease. With an improved understanding of the pathophysiology of SCD as well as the success of several recently approved drugs for other orphan diseases, there is an increased interest in the development of drugs for SCD. Areas covered:This review summarizes published studies of drug therapies and ongoing trials of novel agents. Expert opinion:The development of drugs with different mechanisms of action offers opportunities for combination and individualized therapy in SCD. In addition to acute pain crisis, the evaluation of other SCD-related complications, exercise capacity, patient reported outcomes and validated surrogate endpoints are necessary to advance drug development. It is important to involve sites in sub-Saharan Africa and India, which have the highest burden of SCD, in trials of novel therapies.
| S-EPMC6411095 | biostudies-literature
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.
| S-EPMC6717563 | biostudies-literature
Project description: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 Food and Drug Administration, with multiple others at various stages of testing. With the limited efficacy of individual agents, combinations of agents will likely be required for optimal outcomes.
| S-EPMC10727073 | biostudies-literature
Project description:Sickle cell disease (SCD) is a monogenetic disorder due to a single base-pair point mutation in the ?-globin gene resulting in the substitution of the amino acid valine for glutamic acid in the ?-globin chain. Phenotypic variation in the clinical presentation and disease outcome is a characteristic feature of the disorder. Understanding the pathogenesis and pathophysiology of the disorder is central to the choice of therapeutic development and intervention. In this special edition for newborn screening for haemoglobin disorders, it is pertinent to describe the genetic, pathologic and clinical presentation of sickle cell disease as a prelude to the justification for screening. Through a systematic review of the literature using search terms relating to SCD up till 2019, we identified relevant descriptive publications for inclusion. The scope of this review is mainly an overview of the clinical features of pain, the cardinal symptom in SCD, which present following the drop in foetal haemoglobin as young as five to six months after birth. The relative impact of haemolysis and small-vessel occlusive pathology remains controversial, a combination of features probably contribute to the different pathologies. We also provide an overview of emerging therapies in SCD.
| S-EPMC7510211 | biostudies-literature
Project description:Sickle cell anaemia (SCA) results from a single mutation in the β globin gene. It is seldom symptomatic in the first semester of life. We analysed the expression pattern of 9 adhesion molecules on red blood cells, in a cohort of 54 SCA and 17 non-SCA very young infants of comparable age (median 144 days, 81-196). Haemoglobin F (HbF) level was unsurprisingly elevated in SCA infants (41.2% ± 11.2) and 2-4 fold higher than in non-SCA infants, yet SCA infants presented significantly decreased Hb level and increased reticulocytosis. Cytometry analysis evidenced a specific expression profile on reticulocytes of SCA infants, with notably an increased expression of the adhesion molecules Lu/BCAM, ICAM-4 and LFA-3, both in percentage of positive cells and in surface density. No significant difference was found on mature red cells. Our findings demonstrate the very early onset of reticulocyte membrane modifications in SCA asymptomatic infants and allow an insight into the first pathological changes with the release of stress reticulocytes expressing a distinctive profile of adhesion molecules.
| S-EPMC4485482 | biostudies-literature
Project description:Sickle cell disease (SCD) is a life-threatening genetic disorder characterized by chronic hemolytic anemia, vascular injury and multiorgan dysfunctions. Over the last few decades, there have been significant improvements in SCD management in Western countries, especially in pediatric population. An early onset of prophylaxis with Penicillin and a proper treatment of the infections have increased the overall survival in childhood. Nevertheless, management of painful episodes and prevention of organ damage are still challenging and more efforts are needed to better understand the mechanisms behind the development of chronic organ damages. Hydroxyurea (Hydroxycarbamide, HU), the only medication approved as a disease-modifying agent by the United States Food and Drug Administration and the European Medicines Agency, is usually under-used, especially in developing countries. Currently, hematopoietic stem-cell transplantation is considered the only curative option, although its use is limited by lack of donors and transplant-related toxicity. SCD symptoms are similar in children and adults, but complications and systemic organ damages increase with age, leading to early mortality worldwide. Experts in comprehensive care of young patients with SCD, especially those approaching the transition age to adulthood, are missing, leading people to rely on urgent care, increasing health care utilization costs and inappropriate treatments. It would be important to establish programs of comprehensive healthcare for patients with SCD from birth to adulthood, to improve their quality and expectancy of life.
| S-EPMC4737690 | biostudies-literature
Project description:The complex, frequently devastating, multi-organ pathophysiology of sickle cell disease has a single root cause: polymerization of deoxygenated sickle hemoglobin. A logical approach to disease modification is, therefore, to interdict this root cause. Ideally, such interdiction would utilize small molecules that are practical and accessible for worldwide application. Two types of such small molecule strategies are actively being evaluated in the clinic. The first strategy intends to shift red blood cell precursor hemoglobin manufacturing away from sickle hemoglobin and towards fetal hemoglobin, which inhibits sickle hemoglobin polymerization by a number of mechanisms. The second strategy intends to chemically modify sickle hemoglobin directly in order to inhibit its polymerization. Important lessons have been learnt from the pre-clinical and clinical evaluations to date. Open questions remain, but this review summarizes the valuable experience and knowledge already gained, which can guide ongoing and future efforts for molecular mechanism-based, practical and accessible disease modification of sickle cell disease.
| S-EPMC6717594 | biostudies-literature
Project description:Sickle cell disease (SCD), considered the most common monogenic disease worldwide, is a severe hemoglobin disorder. Although the genetic and molecular bases have long been characterized, the pathophysiology remains incompletely elucidated and therapeutic options are limited. It has been increasingly suggested that innate immune cells, including monocytes, neutrophils, invariant natural killer T cells, platelets and mast cells, have a role in promoting inflammation, adhesion and pain in SCD. Here we provide a thorough review of the involvement of these novel, major protagonists in SCD pathophysiology, highlighting recent evidence for innovative therapeutic perspectives.
| S-EPMC7012475 | biostudies-literature