Abstract Significance: Sickle cell disease (SCD) is the most common inherited diathesis affecting mostly underserved populations globally. SCD is characterized by chronic pain and fatigue, severe acute painful crises requiring hospitalization and opioids, strokes, multiorgan damage, and a shortened life span. Symptoms may appear shortly after birth, and, in less developed countries, most children with SCD die before attaining age 5. Hematopoietic stem cell transplant and gene therapy offer a curative therapeutic approach, but, due to many challenges, are limited in their availability and effectiveness for a majority of persons with SCD. A critical unmet need is to develop safe and effective novel targeted therapies. A wide array of drugs currently undergoing clinical investigation hold promise for an expanded pharmacological armamentarium against SCD. Recent Advances:Hydroxyurea, the most widely used intervention for SCD management, has improved the survival in the Western world and more recently, voxelotor (R-state-stabilizer), l-glutamine, and crizanlizumab (anti-P-selectin antibody) have been approved by the Food and Drug Administration (FDA) for use in SCD. The recent FDA approval emphasizes the need to revisit the advances in understanding the core pathophysiology of SCD to accelerate novel evidence-based strategies to treat SCD. The biomechanical breakdown of erythrocytesis, the core pathophysiology of SCD, is associated with intrinsic factors, including the composition of hemoglobin, membrane integrity, cellular volume, hydration, andoxidative stress. Critical Issues and Future Directions: In this context, this review focuses on advances in emerging nongenetic interventions directed toward the therapeutic targets intrinsic to sickle red blood cells (RBCs), which can prevent impaired rheology of RBCs to impede disease progression and reduce the sequelae of comorbidities, including pain, vasculopathy, and organ damage. In addition, given the intricate pathophysiology of the disease, it is unlikely that a single pharmacotherapeutic intervention will comprehensively ameliorate the multifaceted complications associated with SCD. However, the availability of multiple drug options affords the opportunity for individualized therapeutic regimens tailored to specific SCD-related complications. Furthermore, it opens avenues for combination drug therapy, capitalizing on distinct mechanisms of action and profiles of adverse effects. Keywords: R-state stabilizers; antisickling agents; combination drug therapy; fetal hemoglobin; oxygen affinity; red blood cell; sickle cell disease. Full Article: https://pubmed.ncbi.nlm.nih.gov/37975291/

Chronic pain is the most common complication affecting adults with sickle cell disease (SCD).1 Pain profoundly affects people’s quality of life, functional ability, and health care utilization. Clinicians are often unsuccessful at addressing chronic pain in SCD, especially among the large number of patients for whom nonopioid analgesics aren’t sufficient and those who have developed opioid tolerance. Why aren’t we doing better? We believe the medical community is looking at sickle cell pain through the wrong lens — treating it as a hematologic problem, while overlooking the neurologic, psychological, and social aspects of chronic pain. Given the current understanding of the neuropsychology of pain, the health care system has the ability to manage sickle cell pain more effectively. Doing so will require accepting a broader understanding of the experience of pain and devoting adequate resources to addressing its multiple dimensions. The biopsychosocial model helps capture people’s experience of chronic pain by affirming that biologic, neuropsychological, and socioenvironmental elements play a role in pain-related processes. Biologically, acute vaso-occlusive events in SCD cause tissue inflammation and nociceptive pain. This concept remains the primary model used in clinical practice to understand sickle cell pain and justify analgesic therapy. Many adults with SCD, however, have chronic daily pain without indicators of vaso-occlusive pain. Adults with a chronic-pain phenotype have nerve damage, chronic inflammation, and sometimes central sensitization. They frequently have allodynia and hyperalgesia. Even patients who have received successful curative therapies, such as a bone marrow transplant or gene therapy, may continue to have chronic pain. These findings suggest that chronic pain in adults with SCD is complex and that a model based principally on hematologic processes is inadequate for understanding and managing it. Chronic pain that is affected by neuropsychological factors is common to many disease processes, and the medical field’s understanding of the basis for this type of pain has advanced over the past decade. Prolonged or repeated episodes of nociceptive pain result in neural changes that enhance pain sensitivity, heighten pain anticipation and aversion, and cause synaptic networks involved in emotion and cognition to prioritize painful stimuli over pleasurable ones. In addition, emotional trauma associated with pain experienced on a single occasion can enhance negative emotions during future episodes. All these factors contribute to a subjective experience of pain as prolonged, persistent, overwhelming, and urgent, even in the absence of nociceptive stimuli. How is this experience reflected in common health care scenarios? One hypothetical example involves an adult with SCD who is being treated with long-term opioid therapy and comes to an emergency department with severe pain. If she appears to be in distress and her diagnostic tests suggest acute vaso-occlusive pain, she will probably be admitted for treatment and receive analgesics adjusted to a dose to relieve her pain. If she doesn’t display the expected signs of distress, and if her lab work doesn’t support a diagnosis of a vaso-occlusive event, however, there is a good chance that she will be labeled as “drug seeking.” This label, which delegitimizes the patient’s account of her pain, is powerful. Once she is labeled a “drug seeker,” the patient may be sent home without treatment at the physician’s discretion. This scenario illustrates why relying on the hematologic model of sickle cell pain provides insufficient guidance for clinical decision making. Is the patient exaggerating or falsifying pain if there is no apparent nociceptive stimulus? Does the patient “deserve” aggressive pain treatment? Will opioid treatment help the patient, or will it potentiate a harmful dependence? The hematologic model doesn’t encompass factors affecting pain that derive from experiences with various forms of structural violence, including historical inequity, trauma, and racism. These factors affect not just the life circumstances of adults with SCD, but the neuroanatomy and synaptic processing that underlie their experience of pain. Historically, adults with SCD, the majority of whom are people of color, have been undertreated for chronic pain. Well into the 20th century, the medical profession maintained, without basis, that people of color are less sensitive to pain than White people. In today’s vernacular, labels such as “drug seeker” and “overutilizer” serve to minimize sickle cell pain and dismiss the patient’s reported subjective experience. In semistructured interviews conducted by one of our teams, adults with SCD reported profound distress associated with what should have been a powerful act of self-care: seeking hospital-based administration of parenteral opioids for pain flares. They further reported that racism and bias against SCD are woven into their clinical encounters. These findings, which align with reports from other researchers,2 point to a fundamental tension. Adults with SCD must seek acute pain relief in a White-dominated health care system. The system may arbitrarily grant or refuse their request for pain relief, a reality that embodies racism in that such encounters are marked by White authority over the bodies of people of color. Such experiences are profoundly traumatizing for patients. The harmful effects of the health care system dismissing the pain of adults with SCD go beyond an immediate lack of pain relief for patients. Uncertainty about access to treatment forces patients to devote more cognitive resources and, at the behavioral level, more time and effort, to obtaining pain treatment. Neurologically, the repeated failure of pain-relief efforts enhances awareness of, attention to, and distress caused by nociceptive stimuli and produces a prolonged reduction in the threshold for pain perception. Negative or unpredictable experiences seeking pain relief reinforce the neural processes that give rise to chronic pain. In addition, emotions play a powerful role in learning. A single experience that causes emotional trauma can greatly amplify the degree of distress associated with subsequent pain episodes.3 What adults with SCD seek as patients is relief from pain that is often excruciating. Opioids continue to occupy a central place in the treatment of acute and chronic pain in people with SCD, as reflected in the most recent American Society of Hematology pain guidelines. Treatment must be carefully managed to avoid hyperalgesia, tachyphylaxis, treatment failure, addiction, and accidental overdose. While ensuring that adults with SCD have reliable and unimpeded access to pharmacotherapy, we also need to offer them a broader range of strategies based on medicine’s emerging understanding of the neuropsychological basis of chronic pain.4 Our patients tell us that they want a pain plan that encompasses emotional support, validation, cognitive strategies, and pharmacotherapy. Interventions involving cognitive behavioral techniques, training in mindfulness-based pain management, and multidisciplinary team approaches have reduced pain associated with other chronic conditions. Multilevel interventions that are part of a patient-centered model of pain management could represent a more effective approach to improving quality of life among people with SCD and chronic pain (see box).5 Broadly, the medical community needs to recognize the ways in which patients’ interactions with the health care system create distress and amplify pain and take steps to repair broken care processes. The barriers, delays, and uncertainties that adults with SCD face in obtaining access to pain treatment ultimately intensify their pain and increase the urgency of pain-avoidant behavior, while undermining both patient and institutional goals. The approaches outlined above will require substantial health care system investment. We believe such investment is justified to improve the quality of care for adults with SCD, who have a lifelong, debilitating disease. If we can help them address the many dimensions of their chronic pain effectively, they may begin to perceive the health care system as a resource in managing their disease, rather than an obstacle to realizing improved health and well-being. Full Article: https://www.nejm.org/doi/10.1056/NEJMp2301143

Abstract Sickle cell disease (SCD), a distinctive and often overlooked illness in the 21st century, is a congenital blood disorder characterized by considerable phenotypic diversity. It comprises a group of disorders, with sickle cell anemia (SCA) being the most prevalent and serious genotype. Although there have been some systematic reviews of global data, worldwide statistics regarding SCD prevalence, morbidity, and mortality remain scarce. In developed countries with a lower number of sickle cell patients, cutting-edge technologies have led to the development of new treatments. However, in developing settings where sickle cell disease (SCD) is more prevalent, medical management, rather than a cure, still relies on the use of hydroxyurea, blood transfusions, and analgesics. This is a disease that affects red blood cells, consequently affecting most organs in diverse manners. We discuss its etiology and the advent of new technologies, but the aim of this study is to understand the various types of nutrition-related studies involving individuals suffering from SCD, particularly in Africa. The interplay of the environment, food, gut microbiota, along with their respective genomes collectively known as the gut microbiome, and host metabolism is responsible for mediating host metabolic phenotypes and modulating gut microbiota. In addition, it serves the purpose of providing essential nutrients. Moreover, it engages in direct interactions with host homeostasis and the immune system, as well as indirect interactions via metabolites. Nutrition interventions and nutritional care are mechanisms for addressing increased nutrient expenditures and are important aspects of supportive management for patients with SCD. Underprivileged areas in Sub-Saharan Africa should be accompanied by efforts to define and promote of the nutritional aspects of SCD. Their importance is key to maintaining well-being and quality of life, especially because new technologies and products remain limited, while the use of native medicinal plant resources is acknowledged. Keywords: sickle cell, hemoglobin, anemia, microbiota, nutrition, vaso-occlusive crisis 1. Introduction Sickle cell disease, an often overlooked disease in the 21st century, is a noncontagious and enduring congenital blood disorder. It encompasses a group of clinical syndromes that affect hemoglobin due to a genetic code for abnormal polymerized deoxygenated hemoglobin. This abnormal hemoglobin distorts the shape of red blood cells, and it is inherited by children from their parents [1]. The term sickle cell disease (SCD) is derived from the polymerization of two mutant sickle β-globin subunits leading to a crescent or sickled shape of erythrocytes [2]. Sickle cell disease comprises various genotypes, yielding a group of hemoglobinopathies [3]. The production of hemoglobin is regulated by the inheritance of a pair of genes, but there is considerable variability in absolute hemoglobin levels among patients with SCD [4]. Sickle cell anemia results from the inheritance of two sickle genes, with one gene from each parent [5,6]. Two parts, heme and globin, constitute the normal form of hemoglobin. The protein is made up of four polypeptide chains (two α chains and two β chains). There are many known mutations in the hemoglobin subunit β-HBB (β-globin protein) coding gene, which make up the most common form of hemoglobin in adult humans, hemoglobin A (HbA) [7]. A variety of inherited diseases arise from these mutations. Abnormal versions of β-globin, such as hemoglobin C (HbC), hemoglobin E (HbE), and hemoglobin S (HbS), are produced by a variant mutation in the HBB gene. It is this mutation in the HBB gene that causes sickle cell anemia [8]. Sickle cell anemia (SCA) is the most prevalent and serious genotype of SCD, followed by HbSC (“mild” form of SCA), hemoglobin (Hb) Sβ thalassemia, HbSβ+thalassemia (accounting for some 30–40% of SCD patients), and other rare and benign genotypes [9,10]. Sickled red blood cells are susceptible to chronic hemolysis [11], and emerging evidence reveals that SCD is made evident by the presence of chronic inflammation and oxidative stress, both of which play a role in the development of chronic vasculopathy and several other enduring complications [12]. SCA, characterized by abnormal red blood cells and hemoglobin, is worsened by low oxygen levels in the air [13]. SCA is manifested as the result of the presence of an autosomal recessive allele, which is found on the short arm of chromosome 11p15.5 [14]. This alteration of the genetic code leads to the substitution of a single amino acid, where valine replaces glutamic amino acid in the sixth position of the 146 amino acids of the β chain of hemoglobin [5] (Figure 1). After more than one hundred years since the discovery of sickle cell group of hemoglobinopathies as genetically inherited diseases [15], new studies are still necessary to explore the molecular mechanisms leading to fetal hemoglobin induction and find ways to reduce the adverse effects in patients with SCA and other β-hemoglobinopathies [16]. There are both severe and mild SCD genotypes, which reflect the type of symptoms and prognoses for the disease. Research has been conducted during routine patient care to identify possible clinical biomarkers among SCD patients. These biomarkers may vary according to genotype and treatment categories. However, there is still insufficient progress in developing treatment options or counseling decisions [17,18,19]. Sickle-shaped red blood cells are more rigid and stickier, which leads to the obstruction of small blood vessels. This obstruction prevents oxygen from reaching body tissues and organs, inducing both acute and chronic intense pain. There is little research focusing on the pathophysiology of acute or chronic pain in SCD, and therefore it is still poorly understood. However, it is believed to be dependent on the interaction of several molecular mechanisms [2,20,21]. 1.1. The Incidence of Sickle Cell Disease This disease substantially induces multimorbidity and impairs quality of life, while placing strain on healthcare systems wherever it exists [22,23]. The global burden of this disease has been assessed [24], highlighting the high risk of child mortality associated with SCA. In Sub-Saharan Africa, it can contribute to as much as 90% of under-5 mortality [25,26], with approximately 500 children with SCD continuing to die prematurely every day [27]. This is due to delayed diagnosis and/or the lack of access to comprehensive care, a trend that urgently needs to be reversed [9]. Every year, between 300,000 and 400,000 newborns with SCA are delivered around the world, whereas tens of thousands of people show the homozygosity for hemoglobin S form, which represents the most severe clinical phenotype of the disease [28]. Although SCD occurs worldwide, Sub-Saharan Africa is the region with the highest prevalence. It is estimated that approximately 1000 children with SCD are born in Africa every day, and more than 500 of them die before reaching the age of 5 years [29]. Children suffer several preventable chronic disorders that are followed by premature death associated with SCD. Efforts have been made to identify achievable goals to improve outcomes both in the short and long term. These initiatives aim to recitfy the present unfair attention given to this inherited condition, particularly in developing countries [30]. Approximately 1 in 12 African Americans carries the SCD mutation, and 1 in 500 African Americans suffers from the disorder. In the U.S., 1 out of every 16,300 Hispanic-American neonates is born with SCA each year [31]. Epidemiological data on all blood disorders is still scarce, but SCD is estimated to affect approximately 250 million people globally. Despite the increase in the global burden of SCD, which is believed to affect over 20 million people [32], including an estimated 200,000 annual sickle genotype births in Sub-Saharan Africa [33], available data on SCA prevalence, morbidity, and mortality remains limited on a global scale. However, some systematic reviews on global data exist [34,35]. Different areas in Côte d’Ivoire, Egypt, Lake Chad, Sudan, Lake Victoria, the coast of Kenya, Tanzania, Mozambique, and the east coast of Madagascar have been projected to have a a predicted HbS allele frequency between 7.5% and 12.5% [36]. In northern Mozambique, hematological studies have revealed a prevalence of sickle cell trait (HbAS) and G6PD (glucose-6-phosphate dehydrogenase) deficiency to be around 4% [37,38]. Sickle cell trait (HbAS) is notably more common in West Africa. It is very interesting and well-known that carriers of the sickle cell trait HbAS experience natural and nearly complete protection against severe Plasmodium falciparum malaria. This protection is observed despite the inadequately understood relationships between HbAS, malaria, and other common causes of child mortality [39,40,41,42]. 1.2. Sickle Cell Disease Physiopathology When cells are subjected to physiological stressors, they react with a mechanism described as the heat shock response. This mechanism activates a certain type of critical molecular regulator called heat shock proteins (HSPs) [43]. Heme oxygenase 1 is a member of the heat shock protein (HSP32) family and is involved in numerous cellular operations [44]. Increased heme in SCD causes the upregulation of heme oxygenase 1, which leads to cardiomyopathy through ferroptosis, an iron-dependent nonapoptotic form of cell death [45]. This enhances the fact that both genetic and environmental factors affect the process. Thus, the understanding of biomarkers and the molecular basis of diseases such as SCA are significant in playing a definitive role on the onset of such pathologies and, therefore, on the prevention strategies [46,47]. This leads to the formation of hemoglobin S and the change to sickle-shaped red blood cells compared to normal red blood cells. These cells obstruct the bloodstream, hence leading to serious problems, including cerebrovascular accident, nephropathy, retinopathy, infections, aches, and pains [48] (Figure 2). Among the four DNA bases (two purines: adenine and guanine, two pyrimidines: thymine and cytosine), guanine has the lowest redox potential and is preferentially targeted for oxidation [49]. Despite guanine reduced redox potential, guanine radicals are known to trigger mutations and damage the genetic code, which are involved in carcinogenesis and ageing [50]. Because SCD is hallmarked by an underlying chronic inflammatory status, which is partly driven by proinflammatory M1 macrophages [51], heme scavenging or modulation, as well as the potential therapeutic targeting of mitochondrial biogenesis, might significantly ameliorate tissue damage associated with SCD pathophysiology [52]. Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1α), a transcriptional coactivator protein that regulates the genes involved in energy metabolism [53], exerts significant control over, induces, and coordinates gene expression. It stimulates mitochondrial oxidative metabolism (i.e. respiratory capacity, oxidative phosphorylation, and fatty acid β-oxidation), produces ATP and lipids, induces amino acid and heme biosynthesis, and generates/sequesters reactive oxygen species (ROS) [54]. 1.3. Sickle Cell Disease Diagnosis Sickle cell disease can be prevented prenatally, and it can also be diagnosed in utero or in the newborn period through screening. Early diagnosis of this condition is essential for beginning treatments that can reduce the risk of life-threatening complications, such as severe infections and strokes, as well as managing the disease effectively to reduce morbidity. SCD is diagnosed through a simple complete blood test, peripheral blood smears, hemoglobin electrophoresis, HPLC, and various genetic sickling tests. Hemoglobin S solubility assay and sodium metabisulfite test may be used for screening individuals aged 6 months or older. For pregnant women, screening should ideally be conducted before 10 weeks’ gestation. Recent studies have also reviewed current emerging portable techniques that have been developed for the early detection and diagnosis of sickle cell disease and carrier states [55,56,57]. More detailed molecular genetic diagnose testing is also available [58]. 2. The Advent of New Technologies The discovery of CRISPR (clustered regularly interspaced short palindromic repeats) and its function, which took place between 1993 and 2005, marked the recognition of acquired immunity systems that are widespread in archaea and bacteria. This discovery has since been widely validated through the development of CRISPR and CRISPR-associated protein (Cas) systems [59]. As a result of the emergence of genome editing tools, this subject has experience significant growth, with universities, research institutes, biotechnology enterprises, and sizable pharmaceutical companies collaborating to create innovative therapeutics with far-reaching potential [60,61]. Using CRISPR-Cas technology, which is a specific, efficient, and versatile gene editing technology, one can modify, delete, or correct precise regions of DNA [62,63]. However, this gene therapy still needs to be economical, practical, easy, explicit, quick, convenient, safe, and adequately valid to be capable of producing the desired effect [64]. Formerly, gene editing required tissue samples to be removed from the body for editing outside, but now it is possible to use this technology in vivo. Thus, genome editing therapies can be developed to silence “bad” genes [65,66,67]. CRISPR-Cas9, which depends on ribonucleoprotein complexes (RNPs), leverages the subcellular location of mRNAs transported within cells in RNPs and is indeed a powerful tool for targeting and editing DNA [62,68,69]. Since the early 2000s when the identity and clinical functions of microRNAs (miRNAs) [70] were discovered, the roles of miRNAs as potential biomarkers for both diagnosis and prognosis have been actively investigated over the past few decades [6,71,72]. MicroRNAs, which are short noncoding genetic material implicated in the modulation of mitochondrial activity and homeostasis, also contribute to the readjustment of cell metabolism, offering a new perspective on the regulation of gene expression following transcription [73]. They act by enhancing the activity of apoptosis-inducing factors and by targeting and eventually silencing specific genes. This silencing process involves known oncogenes and disease suppressor genes related to metabolic signaling pathways and is associated with genetic disorders [73,74]. Patients with high fetal hemoglobin (HbF) status, which is a product of γ-globin genes and modulates SCD, experience fewer painful crises and enhanced survival rates [75]. Examining the factors that control γ-globin genes at both transcriptional and translational levels, including miRNAs, can assist in the identification of possible therapeutic avenues for SCD [76,77]. Some miRNAs have the potential to serve as valuable molecular tools for innovative therapeutic approaches in hemoglobinopathies, especially in the context of hematogenesis, erythrocyte cell differentiation, and degree of anemia severity. Using these miRNAs could ameliorate the clinical framework of SCA [78]. Patients with SCD often display abnormal triggering of the innate component of the immune system’s natural defense pathway, leading to higher risks of infection and predisposing patients to autoimmune diseases [79]. The future of medical research will be to focus on the identification and development of noninvasive biomarkers for specific diseases. However, it is still uncertain which miRNAs, or combinations of multiple biomarkers, could be the most prominent candidates for discovery and development [80]. 3. Current Treatments of Sickle Cell Disease A definitive cure for sickle cell anemia (SCA) remains a subject of debate. In this review, we only aim to summarize current trends and knowledge regarding available treatments for SCD and to emphasize the fact that there is a substantial unmet need for medicines. We will also provide a brief overview on existing therapeutic interventions worldwide, which are largely limited to blood transfusions. Increasing the production of fetal hemoglobin (HbF) in significant quantities can diminish the severity of the clinical progression in β-thalassemia and SCD. This can lead to a decrease in morbidity, disability, impairment, illness, and mortality [81]. There are science-based guidelines elaborated by the American Society of Hematology (ASH) designed to support patients, clinicians, and other healthcare professionals, namely, in pain management decisions for children and adults with SCA. However, these do not provide specific guidance on nutritional care and other strategies [82,83]. SCD is caused by a mutation that results in the substitution of glutamic acid for valine. Despite many gaps in our understanding of the biological mechanisms of glutamine and its therapeutic implications, the FDA approved L-glutamine (10–30 g/day oral powder, twice daily) in 2017 for individuals aged 5 and older to lower the number of pain crises [84]. Until recently, only the use of an oral chemotherapeutic drug, hydroxycarbamide (also known as hydroxyurea), was considered for the treatment of SCD. Hydroxyurea, which is a ribonucleotide reductase, is the only approved drug for disease-modifying treatment in patients with SCA [85]. However, it is currently underutilized in clinical practice [86]. A class of new medications called hemoglobin S (HbS) polymerization inhibitors (e.g., voxelotor), has been recently approved by the FDA in 2019 and by the E.U. EMA in 2022. These drugs are intended for the oral treatment of hemolytic anemia due to SCD and vaso-occlusive crisis (VOC), in adults and children aged 12 years and older [87]. This small-molecule drug is able to attach to and stabilize hemoglobin, preventing hemoglobin polymerization (i.e., formation of abnormal hemoglobin) that causes the formation of sickle shaped red blood cells [88]. In well-resourced countries, three potential treatments are available for preventing or reducing the morbidity and mortality associated with SCA: transfusions, hydroxyurea, and stem cell transplantation [89]. There is no evidence of any benefits of corticosteroid use in SCD acute events [90]. The polymerization of abnormal hemoglobin S upon deoxygenation in the tissues to form fibers in red cells causes the development of SCD, thus, generating deformations and blockages in the circulation. Hence, many attempts have been made to find drugs that can control nonpolymerizing fetal hemoglobin [88]. Vaso-occlusive crisis has been prevented and treated using an approved drug called crizanlizumab. This drug is designed to treat pain by preventing blood cells from sticking to the inner walls of blood vessels. The monthly administration of this monoclonal antibody against P-selectin (mediator of inflammation through promoting adherence of leukocytes to activated platelets and endothelium) has proven effective in lowering the frequency of sickle pain crises [91]. There is a hypothesis, which requires further investigation, suggesting that leucine transcriptional nuclear factor NRF2 activation with sulforaphane (a chemical compound found in vegetables such as broccoli and Brussels sprouts), may offer therapeutic benefits for SCD patients. These potential benefits could include reducing liver damage, restoring oxidative capacity, and increasing fetal hemoglobin concentration [92]. Allogeneic hematopoietic stem cell transplantation, also referred to as bone marrow transplant, has been known to cure severe congenital anemias. This treatment has been used to transplant healthy hematopoietic stem cells, obtained from several sources, into patients with dysfunctions related to many malignant and nonmalignant disorders [93] (Table 1). Full Article: https://pmc.ncbi.nlm.nih.gov/articles/PMC10820494/