Are genetic approaches still needed to cure sickle cell disease?
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ABSTRACT:
SUBMITTER: Brodsky RA
PROVIDER: S-EPMC6934198 | biostudies-literature | 2020 Jan
REPOSITORIES: biostudies-literature
Publications
Are genetic approaches still needed to cure sickle cell disease?
Brodsky Robert A RA DeBaun Michael R MR
The Journal of clinical investigation 20200101 1
Similar Datasets
Project description:Sickle cell disease (SCD) is an inherited blood disorder, due to a single point mutation in the β-globin gene (HBB) leading to multisystemic manifestations and it affects millions of people worldwide. The monogenic nature of the disease and the availability of autologous hematopoietic stem cells (HSCs) make this disorder an ideal candidate for gene modification strategies. Notably, significant advances in the field of gene therapy and genome editing that took place in the last decade enabled the possibility to develop several strategies for the treatment of SCD. These curative approaches were firstly based on the correction of disease-causing mutations holding the promise for a specific, effective and safe option for patients. Specifically, gene-editing approaches exploiting the homology directed repair pathway were investigated, but soon their limited efficacy in quiescent HSC has curbed their wider development. On the other hand, a number of studies on globin gene regulation, led to the development of several genome editing strategies based on the reactivation of the fetal γ-globin gene (HBG) by nuclease-mediated targeting of HBG-repressor elements. Although the efficiency of these strategies seems to be confirmed in preclinical and clinical studies, very little is known about the long-term consequences of these modifications. Moreover, the potential genotoxicity of these nuclease-based strategies must be taken into account, especially when associated with high targeting rates. The recent introduction of nuclease-free genome editing technologies brought along the potential for safer strategies for SCD gene correction, which may also harbor significant advantages over HBG-reactivating ones. In this Review, we discuss the recent advances in genome editing strategies for the correction of SCD-causing mutations trying to recapitulate the promising strategies currently available and their relative strengths and weaknesses.
| S-EPMC10652763 | biostudies-literature
Project description:Effective medical management for sickle cell disease (SCD) remains elusive. As a prevalent and severe monogenic disorder, SCD has been long considered a logical candidate for gene therapy. Significant progress has been made in moving toward this goal. These efforts have provided substantial insight into the natural regulation of the globin genes and illuminated challenges for genetic manipulation of the hematopoietic system. The initial γ-retroviral vectors, next-generation lentiviral vectors, and novel genome engineering and gene regulation approaches each share the goal of preventing erythrocyte sickling. After years of preclinical studies, several clinical trials for SCD gene therapies are now open. This review focuses on progress made toward achieving gene therapy, the current state of the field, consideration of factors that may determine clinical success, and prospects for future development.
| S-EPMC4760089 | biostudies-literature
Project description:Sickle cell disease (SCD) had first been mentioned in the literature a century ago. Advancement in the molecular basis of the pathophysiology of the disease opens the door for various therapeutic options. Though life-extending treatments are available for treating patients with SCD, allogeneic hematopoietic stem cell transplantation (HSCT) is the only option as of yet. A major obstacle before HSCT to cure patients with SCD is the availability of donors. Matched sibling donors are available only for a small percentage of patients. To expand the donor pool, different contrasting approaches of allogeneic HSCT like T-cell replete and deplete have been tested. None of those tested approaches have been without the risk of GvHD and graft rejection. Other limitations such as transplantation-related infections and organ dysfunction caused by the harsh conditioning regimen need to be addressed on a priority basis. In this review, we will discuss available allogeneic HSCT approaches to cure SCD, as well as recent advancements to make the approach safer. The center of interest is using megadose T-cell-depleted bone marrow in conjugation with donor-derived CD8 veto T cells to achieve engraftment and tolerance across MHC barriers, under reduced intensity conditioning (RIC). This approach is in phase I/II clinical trial at the MD Anderson Cancer Centre and is open to patients with hemoglobinopathies.
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| S-EPMC9544336 | biostudies-literature
Project description:Sickle cell disease (SCD) is a group of inherited genetic conditions associated with lifelong complications and increased healthcare resource utilization. Standard treatment for SCD in the US varies based on stage of the disease and observed clinical severity. In this study, we aim to evaluate the potential cost-effectiveness of a durable cell or gene therapy cure for sickle cell disease from the US healthcare sector perspective. We developed a lifetime Markov model to evaluate the cost-effectiveness of a hypothetical single-administration durable treatment (DT) for SCD provided at birth, relative to standard of care (SOC). We informed model inputs including direct healthcare costs, health state utility weights, transition probabilities, and mortality rates using a retrospective database analysis of commercially insured individuals and the medical literature. Our primary outcome of interest was the incremental cost-effectiveness ratio (ICER) of DT versus SOC evaluated at a base case willingness-to-pay (WTP) threshold of $150,000 per quality-adjusted life year (QALY). We tested the robustness of our base case findings through scenario, deterministic sensitivity (DSA), and probabilistic sensitivity analyses (PSA). In the base case analysis, treatment with DT was cost-effective with an ICER of $140,877/QALY relative to SOC for a hypothetical cohort involving 47% females. Both males (ICER of $135,574/QALY) and females (ICER of $146,511/QALY) were similarly cost-effective to treat. In univariate DSA the base case ICER was most sensitive to the costs of treating males, DT treatment cost, and the discount rate. In PSA, DT was cost-effective in 32.7%, 66.0%, and 92.6% of 10,000 simulations at WTP values of $100,000, $150,000, and $200,000 per QALY, respectively. A scenario analysis showed cost-effectiveness of DT is highly contingent on assumed lifetime durability of the cure. A hypothetical cell or gene therapy cure for SCD is likely to be cost-effective from the US healthcare sector perspective. Large upfront costs of a single administration cure are offset by significant downstream gains in health for patients treated early in life. We find cost-effectiveness outcomes do not vary substantially by gender; however, several model parameters including assumed durability and upfront cost of DT are likely to influence cost-effectiveness findings.
| S-EPMC8149675 | biostudies-literature
Project description:Sickle cell disease (SCD) is an inherited blood condition resulting from abnormal hemoglobin production. It is one of the most common genetic diseases in the world. The clinical manifestations are variable and range from recurrent acute and debilitating painful crises to life-threatening pulmonary, cardiovascular, renal, and neurologic complications. The only curative treatment of SCD at this time is bone marrow transplantation (also called hematopoietic stem cell transplantation) using healthy blood stem cells from an unaffected brother or sister or from an unrelated donor if one can be identified who is a match in tissue typing. Unfortunately, only a minority of patients with sickle cell has such a donor available. The use of autologous hematopoietic stem cells and alternative types of genetic modifications is currently under study in clinical research trials for this disease. The approaches include the use of viral vectors to express globin genes that are modified to prevent sickle hemoglobin polymerization or to express interfering RNAs to "flip the switch" in adult red cells from adult β-sickle hemoglobin to fetal hemoglobin using a physiologic switch, and several gene editing approaches with the goal of inducing fetal hemoglobin or correcting/modifying the actual sickle mutation. In this audio review, we will discuss these different approaches and review the current progress of curative therapy for SCD using gene therapy.
| S-EPMC9153042 | biostudies-literature
Project description:Survival for patients with SCD has been prolonged by improvements in supportive care, including vaccinations, antibiotic prophylaxis, and overall medical management, including tra nsfusion. However, there remains only one approved, partially effective drug for sickle cell disease-hydroxyurea (hydroxycarbamide). The world desperately needs better ways of both treating and preventing the recurrent painful vaso-occlusive episodes pathognomonic of sickle cell disease as well as the end-organ damage that still leads inexorably to severely shortened life expectancies throughout the world. Based on accumulating knowledge about how the abnormal red blood cells of sickle cell disease cause the double scourge of acute painful episodes and progressive end-organ damage, both pharmaceutical enterprises and individual investigators are now pursuing multiple new avenues for treating sickle cell disease. As a result, many compounds are in active development, both in preclinical models as well as in phase I, II, and III clinical trials. These agents target many pathophysiologic processes thought to be critical in sickle cell disease, including the chemical and physical behavior of haemoglobin S, cell adhesion, coagulation pathways, platelet activation, inflammatory pathways, and upregulation of haemoglobin F expression. In addition, recent explorations of the genetic variations that predispose to certain types of sickle cell disease-related tissue injury, such as stroke or nephropathy, are expected to lead to identification of drugs targeting the pathways uncovered by such work. Thus, the next five to ten years holds a promise of new treatments for sickle cell disease.
| S-EPMC5418585 | biostudies-literature
Project description:Sickle cell anemia is associated with unusual clinical heterogeneity for a Mendelian disorder. Fetal hemoglobin concentration and coincident α thalassemia, both which directly affect the sickle erythrocyte, are the major modulators of the phenotype of disease. Understanding the genetics underlying the heritable subphenotypes of sickle cell anemia would be prognostically useful, could inform personalized therapeutics, and might help the discovery of new "druggable" pathophysiologic targets. Genotype-phenotype association studies have been used to identify novel genetic modifiers. In the future, whole genome sequencing with its promise of discovering hitherto unsuspected variants could add to our understanding of the genetic modifiers of this disease.
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Project description:To address the global burden of sickle cell disease and the need for novel therapies, the American Society of Hematology partnered with the US Food and Drug Administration to engage the work of 7 panels of clinicians, investigators, and patients to develop consensus recommendations for clinical trial end points. The panels conducted their work through literature reviews, assessment of available evidence, and expert judgment focusing on end points related to patient-reported outcome, pain (non-patient-reported outcomes), the brain, end-organ considerations, biomarkers, measurement of cure, and low-resource settings. This article presents the findings and recommendations of the end-organ considerations, measurement of cure, and low-resource settings panels as well as relevant findings and recommendations from the biomarkers panel.
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