Emerging therapies in sickle cell disease

Nardo‐Marino, Amina; Brousse, Valentine; Rees, David C.

doi:10.1111/bjh.16504

Cited by 32 publications

(29 citation statements)

References 86 publications

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“…The inhibition appears to proceed through the free radical nitroxide metabolite of hydroxyurea, which quenches the tyrosyl free radical at the active site of the M2 protein subunit of the enzyme [ 190 , 191 ]. Hydroxyurea is also used in the treatment of sickle cell anemia and thalassemia intermedia, by increasing fetal hemoglobin synthesis which reduces the polymerization of sickle cell hemoglobin and the level of RBC transfusions, respectively [ 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 ]. Hydroxyurea has been recently identified as a natural product with possible antiviral and other applications [ 201 , 202 , 203 ].…”

Section: Biologic and Physiological Implications Of Interactions Wmentioning

confidence: 99%

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Kontoghiorghes

Kontoghiorghe

2020

Cells

113

174

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Iron is essential for all living organisms. Many iron-containing proteins and metabolic pathways play a key role in almost all cellular and physiological functions. The diversity of the activity and function of iron and its associated pathologies is based on bond formation with adjacent ligands and the overall structure of the iron complex in proteins or with other biomolecules. The control of the metabolic pathways of iron absorption, utilization, recycling and excretion by iron-containing proteins ensures normal biologic and physiological activity. Abnormalities in iron-containing proteins, iron metabolic pathways and also other associated processes can lead to an array of diseases. These include iron deficiency, which affects more than a quarter of the world’s population; hemoglobinopathies, which are the most common of the genetic disorders and idiopathic hemochromatosis. Iron is the most common catalyst of free radical production and oxidative stress which are implicated in tissue damage in most pathologic conditions, cancer initiation and progression, neurodegeneration and many other diseases. The interaction of iron and iron-containing proteins with dietary and xenobiotic molecules, including drugs, may affect iron metabolic and disease processes. Deferiprone, deferoxamine, deferasirox and other chelating drugs can offer therapeutic solutions for most diseases associated with iron metabolism including iron overload and deficiency, neurodegeneration and cancer, the detoxification of xenobiotic metals and most diseases associated with free radical pathology.

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Section: Biologic and Physiological Implications Of Interactions Wmentioning

confidence: 99%

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Kontoghiorghes

Kontoghiorghe

2020

Cells

113

174

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“…Studies have documented the mortality and morbidity in the form of varied clinical episodes in SCD patients 5 . However, several efficacious interventions are available to improve the life expectancy and quality of life through reducing risks of stroke, pulmonary complications and pain crisis among SCD patients 6–8 …”

Section: Introductionmentioning

confidence: 99%

“…However, some of the Indian states incorporated a few strategies. These strategies have been proved effective elsewhere, in the management of crisis and improving the quality of life 8,19 …”

Section: Introductionmentioning

confidence: 99%

“…Simple therapies like using hydroxyurea are available and can be used in the primary health care level to manage painful crisis among SCD patients. It is proven to be safe and efficacious 8,37,38 . However, toxicity associated with the use of hydroxyurea was reported by some studies 39 .…”

Section: Introductionmentioning

confidence: 99%

“…The tertiary care facilities such as district‐level and medical college hospitals are capable of treating serious episodes of crisis and other complications of SCD. Several treatment modalities are emerging for the management of crisis and improving the quality of life among SCD patients 8 . The health system should be ready to adopt these strategies to tackle this public health problem.…”

Section: Introductionmentioning

confidence: 99%

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Beyond the screening: The need for health systems intervention for prevention and management of sickle cell disease among tribal population of India

Geethakumari

Kusuma

Babu

2020

Health Planning & Management

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Globally, sickle cell disease (SCD) is one of the major public health problems. In India, it is more prevalent in tribal communities. Tribal communities are socio‐economically disadvantaged and constitute 8.6% of India's population. The health and health care seeking of these communities is very poor. Though efficacious interventions are available to manage SCD, they are not reaching these people and no comprehensive programme is in place. The objective of this analysis is to demonstrate the burden of SCD among the tribes in two Indian states of Andhra Pradesh and Telangana, as a case and to highlight the need for public health intervention and health systems strengthening in the country to prevent and manage SCD. One in 10 persons of tribal population of these states carries Hb S gene. A substantial number of children are born every year with the condition. Mostly, the research is limited to screening. Hence, a programme with early detection and an appropriate referral system should be developed. The primary health care system should be strengthened to screen and manage SCD persons with good disease management practices and appropriate community mobilisation activities. The programme should partner with traditional healers and community leaders. People should be encouraged to seek treatment; and counselling for prevention. The study warrants human‐centric approaches during the interventions to address the possible threat of fear of being stigmatised. Thus, the transition of evidence‐based interventions into the programme and practice can improve the lives of people with SCD, particularly the tribal population.

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Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: A phase 2, open‐label study

et al. 2022

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Sickle cell disease (SCD) is one of the most common and debilitating inherited blood disorders affecting millions of people worldwide. SCD is characterized by a single nucleotide mutation in the β-globin gene, HBB:c.20A>T (p.Glu6Val), leading to the production of sickle hemoglobin (HbS). HbS polymerization upon deoxygenation results in poorly deformable sickled red blood cells (RBCs) with a shortened lifespan. These RBCs cause extremely painful vaso-occlusive crises (VOCs), chronic hemolytic anemia, and progressive end-organ damage. 1 New therapeutic options have evolved very slowly despite the medical need for safe and effective therapies that both reduce VOCs and improve anemia. None of the US Food and Drug Administration (FDA) approved therapies for SCD are universally effective nor globally available, and they are limited by their drug costs and safety profiles. 2 Mitapivat (AG-348), an investigational, first-in-class, oral, small-molecule allosteric activator of pyruvate kinase (PK), holds promise as an antisickling agent in addition to its use in PK deficiency (US FDA approved Pyrukynd ® USPI, 2022; NCT02476916, NCT03548220, NCT03559699, NCT03853798), and thalassemia (NCT03692052, NCT04770779, NCT04770753). 3 PK is a key enzyme in RBC metabolism, generating adenosine triphosphate (ATP) to maintain energy homeostasis, thereby membrane integrity and deformability, and modulating 2,3-DPG levels (Figure S1). In SCD, an important metabolic feature directly associated with HbS polymerization is an increased intracellular 2,3-DPG level which promotes deoxygenation of hemoglobin (Hb) by lowering its oxygen affinity. 4 Ex vivo treatment of RBCs of SCD patients with mitapivat restored PK activity and thermostability, increased ATP/2,3-DPG ratio, and markers of RBC sickling. 5 Based on this and phase 1 study results (NCT04000165), 3 we hypothesized that increased glycolytic flux through treatment with mitapivat decreases 2,3-DPG levels and increases ATP levels, thereby inhibiting HbS polymerization, RBC sickling, and ameliorating hemolytic anemia in patients with SCD.

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Emerging therapies in sickle cell disease

Cited by 32 publications

References 86 publications

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Iron and Chelation in Biochemistry and Medicine: New Approaches to Controlling Iron Metabolism and Treating Related Diseases

Beyond the screening: The need for health systems intervention for prevention and management of sickle cell disease among tribal population of India

Safety and efficacy of mitapivat, an oral pyruvate kinase activator, in sickle cell disease: A phase 2, open‐label study

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