Fetal haemoglobin induction in sickle cell disease

Paikari, Alireza; Sheehan, Vivien A.

doi:10.1111/bjh.15021

Cited by 62 publications

(55 citation statements)

References 107 publications

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“…94 Researchers have proposed that interference with or depletion of DNMT1 might prevent the switchoff of hemoglobin F production. [95][96][97][98][99][100] The drug decitabine and its prodrug 5azacytidine have been found to deplete DNMT1 levels. 101 In animals, 5-azacytidine produced increases in hemoglobin F levels up to 20 times those produced by hydroxyurea, even in animals that derived minimal benefit from hydroxyurea by being poor responders.…”

Section: Treatment Of Sickle Cell Disease Hemoglobin F Productionmentioning

confidence: 99%

Sickle Cell Disease: Advances in Treatment

Gardner

2018

TOJ

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Background: Sickle cell disease causes significant morbidity and mortality and affects the economic and healthcare status of many countries. Yet historically, the disease has not had commensurate outlays of funds that have been aimed at research and development of drugs and treatment procedures for other diseases. Methods: This review examines several treatment modalities and new drugs developed since the late 1990s that have been used to improve outcomes for patients with sickle cell disease. Results: Targeted therapies based upon the pathophysiologic mechanisms of sickle cell disease that result in organ dysfunction and painful episodes include hydroxyurea, L-glutamine, crizanlizumab, and other drugs that are currently on the market or are on the verge of becoming available. These agents have the potential to improve survival and quality of life for individuals with sickle cell disease. Also discussed is stem cell transplantation that, to date, is the only curative approach for this disease, as well as the current status of gene therapy. Conclusion:These examples demonstrate how the current knowledge of sickle cell disease pathophysiology and treatment approaches intersect. Although interest in sickle cell research has blossomed, many more clinical trials need to be initiated and subjected to more strenuous examination and analysis than have been used in the past.

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Section: Treatment Of Sickle Cell Disease Hemoglobin F Productionmentioning

confidence: 99%

Sickle Cell Disease: Advances in Treatment

Gardner

2018

TOJ

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“…Hydroxyurea increases HbF levels that inhibit the polymerization of HbS [7,70,[73][74][75][76]. However, its use is hampered by concerns of myelotoxicity and waning effectiveness over time [7,74,[76][77][78]. A 2-year, phase 3 randomized clinical trial using the BABY HUG cohort evaluated the effect of hydroxyurea versus placebo on measured GFR in 193 infants and found no significant effect [65].…”

Section: Current Therapies For Scn (Table 4)mentioning

confidence: 99%

Sickle Cell Nephropathy in the Pediatric Population

et al. 2018

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Background: Compared to the past, patients with sickle cell disease (SCD) currently live longer due to improvements in diagnosis and comprehensive care. Due to these advances, long-term chronic complications pose a greater challenge in the management of patients with SCD. In particular, sickle cell nephropathy (SCN) is associated with significant morbidity and mortality across all age groups. Furthermore, SCN is an understudied condition with relatively few symptoms and therefore requires close surveillance. In this review, we sought to explore the epidemiology, natural history, and treatment options for SCN with an emphasis on the pediatric population. Summary: SCN invariably begins in childhood with evidence of structural changes detected as early as infancy. These indolent changes can progress undetected to advanced chronic kidney disease by late adolescence or early adulthood. The risk factors for progression are not well defined, but significant albuminuria (which is also the most common presentation in childhood) is a key factor in progression. One of the main challenges in understanding SCN in children is the poor correlation between estimated and measured glomerular filtration rates. Another challenge is the lack of large-scale longitudinal studies that track the clinical outcomes of pediatric patients over time. Several studies aim to identify early biomarkers of SCN in children, as albuminuria presents only following significant chronic damage. The utility of angiotensin converting enzyme inhibitors and hydroxyurea in treating albuminuria is addressed here as well as novel treatments that may be of benefit.

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“…Several drugs are under investigation as HbF-inducing agents. However, up to today, only Hydroxyurea is utilized in the clinic, with many limitations (32). Other strategies for the reactivation of the gamma-globin gene have been based on interventions aimed at modifying hemoglobin switching through genomic modification (1,2).…”

Section: Discussionmentioning

confidence: 99%

Delta-Globin Gene Expression Is Enhanced in vivo by Interferon Type I

et al. 2020

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Beta hemoglobinopathies are widely spread monogenic lethal diseases. Delta-globin gene activation has been proposed as a possible approach for curing these pathologies. The therapeutic potential of delta-globin, the non-alpha component of Hemoglobin A 2 (α2δ2; HbA2), has been demonstrated in a mouse model of beta thalassemia, while its anti-sickling effect, comparable to that of gamma globin, was established some time ago. Here we show that the delta-globin mRNA level is considerably increased in a Deoxyribonuclease II-alpha knockout mouse model in which type 1 interferon (interferon beta, IFNb) is activated. IFNb activation in the fetal liver improves the delta-globin mRNA level, while the beta-globin mRNA level is significantly reduced. In addition, we show that HbA2 is significantly increased in patients with multiple sclerosis under type 1 interferon treatment. Our results represent a proof of principle that delta-globin expression can be enhanced through the use of molecules. This observation is potentially interesting in view of a pharmacological approach able to increase the HbA2 level.

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Fetal haemoglobin induction in sickle cell disease

Cited by 62 publications

References 107 publications

Sickle Cell Disease: Advances in Treatment

Sickle Cell Disease: Advances in Treatment

Sickle Cell Nephropathy in the Pediatric Population

Delta-Globin Gene Expression Is Enhanced in vivo by Interferon Type I

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