Advances in the Treatment of Sickle Cell Disease

Kapoor, Sargam; Little, Jane A.; Pecker, Lydia H.

doi:10.1016/j.mayocp.2018.08.001

Cited by 87 publications

(115 citation statements)

References 138 publications

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“…Critical requirements for effective therapies also include adequate delivery of a putative therapeutic compound to tissues where it is most needed and the assurance that its downstream target is capable of responding. In this regard, as noted by Kapoor et al, 6 strategies employed thus far to deliver NO have been ineffective in SCD, despite the fact that SCD is recognized as a NO-deficiency state. The inefficacy of such therapies may reflect the fact that the requisite elevation in NO concentrations may not be achieved at the needed sites in the vasculature because of rapid binding of delivered NO by HbS or avid consumption by reactive oxygen species, 8 or because the major downstream target for NO, guanylate cyclase, is relatively dysfunctional in SCD.…”

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confidence: 99%

“…In their timely synthesis of this field, these authors discuss the roles of hydroxyurea, novel antisickling agents, long-term transfusion therapy, hematopoietic stem cell transplant, and gene therapy; they then discuss therapeutic strategies that are under translational exploration including assorted antioxidants, agents that inhibit cellular adhesion, and agents that inhibit platelet activation. 6 That such a spectrum of specific therapeutic strategies, as summarized by Kapoor et al, is currently under examination speaks to the complexity of organ and tissue injury in SCD: namely, SCD involves diverse interdigitating pathogenetic processes that go far beyond RBC sickling itself; indeed, it may be fairly said that SCD involves virtually all major pathogenetic processes implicated in the causation of disease. [7][8][9] The Figure summarizes salient pathogenetic pathways and offers a perspective on how they may interact and summate in provoking tissue injury in SCD.…”

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confidence: 99%

“…Such adherence markedly delays the passage of RBCs through the microvasculature such that their duration of transit is considerably longer than the time needed for the sickling process; the inevitable consequence is that RBC sickling (and vasoocclusion) occur in the microvasculature. 8 These considerations underscore the challenges in devising new therapies for SCD, as pointed out by Kapoor et al 6 Any recruited pathophysiologic process can instigate others that may not only provide a positive feedback to the proximate trigger, but can also elicit more distal and different ones. 8,9 Additionally, the relative contribution of any given step to the overall pathogenesis of tissue injury may not be fully resolved, as would the potential benefit of inhibiting such steps as a therapeutic strategy.…”

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confidence: 99%

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Current, Emerging, and Anticipated Therapies for Sickle Cell Disease

Nath

Rajkumar

2018

Mayo Clinic Proceedings

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confidence: 99%

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Current, Emerging, and Anticipated Therapies for Sickle Cell Disease

Nath

Rajkumar

2018

Mayo Clinic Proceedings

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“…Of the millions of people with SCD, more than 75% are believed to live in Nigeria, Democratic Republic of Congo, and India [5,48,49]. These countries are additionally responsible for about 80% of global newborns having the causative Glu6 to Val6 mutation [50].Recent reviews described different treatment modalities and efforts to develop new drugs targeting SCD [12,51,52]. A number of research attempts have been made to design interventions aimed at modulating the structural properties, aggregation tendencies, and defective O 2 transport properties of sickle hemoglobin.…”

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confidence: 99%

“…Recent reviews described different treatment modalities and efforts to develop new drugs targeting SCD [12,51,52]. A number of research attempts have been made to design interventions aimed at modulating the structural properties, aggregation tendencies, and defective O 2 transport properties of sickle hemoglobin.…”

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Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

2019

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Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30-40 years ago up to more promising 12-and 15-mers under consideration in recent years.Molecules 2019, 24, 4551 2 of 23 with hemoglobin reduces HbS solubility and promotes polymerization, also called sickling [3,4]. This ultimately leads to hampered O 2 binding and transport, impaired erythrocyte morphology and interaction with endothelial surfaces [5,6], premature erythrocyte rupture and anemia, painful vaso-occlusive crisis, a general poor health, and, in many cases, death [7][8][9][10][11].Despite growing understanding of the polymerization of HbS and its effects on red blood cells (RBCs), until very recently, only two drugs-hydroxyurea and L-glutamine-were approved by the United States (US) Food and Drug Administration (FDA) for the management of SCD [12]. Hydroxyurea is the most widely employed drug treatment of sickle cell anemia in different age groups [13][14][15][16][17][18]. While its clinically observed efficacy has been attributed to different effects at the cellular level [19], the most important mechanism of action relates to its ability to induce the production of fetal hemoglobin (HbF), which does not polymerize, and to increase the total concentration of hemoglobin [20,21]. Hydroxyurea remains a viable treatment option for SCD, and the concern of toxicities associated with its administration has largely been limited to side effects that resolve with medication discontinuation [22][23][24][25][26]. There have, however, been certain reports of associated malignancies [27][28][29][30][31][32], but further investigations are needed to categorically confirm these [33]. L-glutamine is the second approved drug treatment [12,34]. While its mechanism of action is not known, and only suggested to involve a reduction of oxidative stress via elevation of the levels of reduced glutathione [35,36], it is clear that it has no effect on hemo...

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Infrequent Resolution of Vaso‐Occlusive Crises in Routine Clinical Care Among Patients Mimicking the Exa‐Cel Trial Population: A Cohort Study of Medicaid Enrollees

Mahesri,

Lee,

Levin

et al. 2024

Clin Pharma and Therapeutics

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The CRISPR‐based gene editing therapy exagamglogene autotemcel (exa‐cel) recently received FDA approval for patients with severe sickle cell disease (SCD). The approval was based on a phase III trial (CLIMB SCD 121), which showed 97% efficacy of this treatment in eliminating vaso occlusive crises (VOCs) for 12 consecutive months. To help contextualize results from this trial, we aimed to investigate the proportion of patients with severe SCD who remain VOC‐free for a 1‐year period in routine clinical care. Using Medicaid claims data (2000–2018), we identified a cohort of patients, 12–35 years old with severe SCD, defined by ≥ 2 VOCs per year for 2 consecutive years, who met other exa‐cel trial inclusion criteria to mimic a trial‐like population. A VOC was identified using ICD diagnosis codes during hospitalization and ER visits. The primary outcome was the proportion of patients with no VOCs during a 1‐year follow‐up. A total of 7,425 patients with severe SCD [mean (SD) age: 20.5 (6.0) years, 54.6% females, 84% African Americans], had a mean of 5.2 VOCs, 5.1 ER visits and 3.5 hospitalizations per year during the baseline period. The proportion of patients with no VOCs during the 1‐year follow‐up was 7.7% (95% confidence interval: 7.1%–8.3%). In conclusion, less than one in 12 patients with severe SCD achieved VOC‐free status within 1 year in routine clinical care. These findings suggest that the high efficacy observed for exa‐cel in the trial, if replicated in routine clinical care, could translate into a significant public health impact.

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Advances in the Treatment of Sickle Cell Disease

Cited by 87 publications

References 138 publications

Current, Emerging, and Anticipated Therapies for Sickle Cell Disease

Current, Emerging, and Anticipated Therapies for Sickle Cell Disease

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

Infrequent Resolution of Vaso‐Occlusive Crises in Routine Clinical Care Among Patients Mimicking the Exa‐Cel Trial Population: A Cohort Study of Medicaid Enrollees

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