Treatment Of Sickle Cell Disease Research Articles

New Insights in the Treatment of Sickle Cell Disease in Childhood

Sickle cell disease encompasses diseases that are pathophysiologically caused by hemoglobin S. The HbS component of total hemoglobin in SCD is normally over 50%. HbS is based on an amino acid substitution at position 6 of the β-globin chain, where glutamic acid is replaced by valine. This substitution replaces a hydrophilic amino acid with a hydrophobic amino acid at an outward-facing position in the h molecule, explaining the reduced water solubility and altered molecular organization of HbS compared to normal hemoglobin. Diseases caused by HbS include homozygous SCD, where both alleles are affected by the sickle cell mutation (SCD-S/S), HbSC disease, where one allele is affected by the sickle cell mutation and the other by the HbC mutation (SCD-S/C), and sickle cell β-thalassemia with mixed heterozygosity for the sickle cell mutation and a β-thalassemia mutation (SCD-S/β-thalassemia). In SCD-S/β-thalassemia, forms are distinguished where the β-thalassemia mutation completely inactivates the affected gene (SCD-S/β0-thalassemia) and forms where the allele with the thalassemia mutation still has residual activity (SCD-S/β+-thalassemia). Rarely, the sickle cell mutation can also be combined with other hemoglobin variants (SCD-S/D, SCD-S/OArab, SCD-S/Lepore). The carrier status for the sickle cell mutation generally has no clinical significance except in extreme situations (e.g., eye trauma or surgeries involving cardiopulmonary bypass). Carriers have a normal life expectancy. However, there are individual reports of complications in heterozygous carriers of the sickle cell mutation under common circumstances such as pregnancy, mountain sports, intense physical activity, or air travel. It is also unclear whether the carrier status is associated with an increased rate of kidney complications. Nevertheless, it is not appropriate to indicate specific medical care needs based on these individual case reports given the frequency of carrier status. However, the familial risk of developing SCD should be considered in adult carriers. This manuscript focus on new targets to treat sickle cell anemia in children.

Detection of CRISPR/Cas9-Mediated Fetal Hemoglobin Reactivation in Erythroblasts Derived from Cord Blood-Hematopoietic Stem Cells.

Reactivation of the fetal hemoglobin (HbF) in adult erythroid cells via genome editing is a strategy for the treatment of β-thalassemia and sickle cell disease. In related reports, the reactivation of HbF is regularly examined in erythroblasts which are generated from the adult CD34+ hematopoietic stem and progenitor cells (HSPCs). However, the procurement of adult HSPCs, either from the bone-marrow (BM) or from mobilized peripheral-blood (mPB), is difficult. Cord-blood (CB) is a readily available source of HSPCs. CB-HSPCs, however, produce high quantities of HbF following differentiation into the erythroid lineage-a potential drawback in such studies. Here, we have edited the BCL11A enhancer (a well-characterized HbF-quantitative trait loci or QTL) via CRISPR/Cas9 in order to determine whether HbF reactivation could be detected in CB-HSPC-derived erythroblasts. In the edited erythroblasts, insertion/deletion (indel) frequencies of 74.0-80.4% and BCL11A RNA reduction levels of 92.6 ± 5.1% (P < 0.0001) were obtained. In turn, the γ/β-globin transcript ratios were increased from 11.3 ± 1.1-fold to 77.1 ± 2.0-fold, i.e., by 6.8-fold (P < 0.0001)-and the HbF% levels increased from 34.3% in the control population to 43.5% in the BCL11A edited erythroblasts. Our results suggest that γ-globin/HbF reactivation via genome editing can be detected in CB-HSPCs generated erythroblasts-rendering CB-HSPCs a useful model for similar studies.

Folic Acid in the Treatment of Sickle Cell Disease: A Systematic Review

Folic Acid in the Treatment of Sickle Cell Disease: A Systematic Review

Assessing the Clinical Outcomes of Voxelotor Treatment in Patients with Sickle Cell Disease

The results of Voxelotor treatment in Sickle Cell Disease, as assessed through clinical outcomes, demonstrated its efficacy in reducing hemolysis and improving hemoglobin levels. This effect can be attributed to Voxelotor's inhibition of HbS polymerization, thereby restoring the deformability and compliance of sickle RBCs. Our mathematical model provided mechanistic insights into how altered rheological properties of sickle RBCs impact their flow dynamics in microcirculation. Specifically, we observed that Voxelotor-induced improvements in RBC deformability and compliance lead to enhanced plasma film height in capillaries, promoting smoother blood flow and reducing the risk of vaso-occlusive events. We established a direct relationship between the molecular mechanism of Voxelotor action and its clinical outcomes. The mathematical model served as a bridge, elucidating how Voxelotor-induced changes in sickle RBC mechanics translate to improved microcirculatory flow and reduced vaso-occlusion. This holistic understanding not only validates the therapeutic efficacy of Voxelotor but also underscores the importance of considering biomechanical factors in evaluating treatment outcomes in SCD. Furthermore, this study highlighted the relevance of microfluidics based diagnostic tools in assessing the efficacy of Voxelotor treatment. By leveraging insights from our mathematical model, microfluidics devices can be designed to mimic physiological conditions and effectively evaluate the deformability of sickle RBCs before and after treatment. This integrated approach not only facilitates the development of personalized therapeutic interventions but also accelerates the translation of novel treatments, such as Voxelotor, from preclinical studies to clinical practice for the management of Sickle Cell Disease. Int. J. Appl. Sci. Biotechnol. Vol 12(1): 46-53.

The Use of Natural Products in the Treatment of Sickle Cell Disease

The Use of Natural Products in the Treatment of Sickle Cell Disease

Using the daily rate of rise in hemoglobin S to manage RBC depletion/exchange treatment in sickle cell disease.

Red blood cell exchange is often used prophylactically in patients with sickle cell disease, with the goal to maintain hemoglobin S (HbS) below a target threshold level. We reviewed whether the daily "rate of rise" (RoR) in HbS that occurs between procedures can be used for patient management. For some patients not achieving their HbS goals despite efficient exchanges, the post-procedure hematocrit (Hct) target is increased to potentially suppress HbS production. This case series explores the utility of this approach, other clinical uses of the daily RoR in HbS, and the factors that influence it. A total of 660 procedures from 24 patients undergoing prophylactic RBC depletion/exchange procedures were included. Laboratory values and clinical parameters were collected and used to calculate the daily RoR in HbS. Factors such as Hct or medications that might influence the RoR in HbS were evaluated. The RoR in HbS varied widely between patients but remained relatively stable within individuals. Surprisingly, this value was not significantly influenced by changes in post-procedure Hct or concurrent hydroxyurea use. A patient's average RoR in HbS effectively predicted the pre-procedure HbS at the following visit (R2  = 0.65). The RoR in HbS is a relatively consistent parameter for individual patients that is unaffected by medication use or procedural Hct targets and may be useful in determining intervals between procedures.

Current state of gene therapy in sickle cell disease.

Sickle cell disease (SCD) is a type of hemoglobinopathy due to an autosomal recessive genetic defect, causing significant red cell sickling, multi-organ damage and long-term severe morbidities. Due to its complicated care and the impact on quality of life, a curative treatment for SCD is highly desirable. In recent years, gene therapy is emerging as a curative option for SCD, where autologous haematopoietic stem cells are collected from SCD patients and genetically modified ex vivo to reduce its sickling tendency before reinfusion. Although still largely investigational, a limited number of gene therapy options have been recently granted approval for SCD patients. Published data are still currently limited, but early studies have so far demonstrated the intended outcomes of less vaso-occlusive crisis and haemolysis. Nonetheless, despite its curative potential, larger clinical trials and longer follow-up period are still necessary to evaluate the safety of this treatment option, especially the risk of unintended genetic modifications. Furthermore, SCD patients frequently have limited access to specialty care; hence, the issues of affordability and accessibility to SCD gene therapy must also be addressed for it to benefit the appropriate patient population.

Understanding Knowledge, Attitude, and Practices towards Sickle Cell Disease among Adult Outpatients: Insights from Lira Regional Referral Hospital, Northern Uganda

This study investigates the knowledge, attitude, and practices (KAP) regarding sickle cell disease (SCD) among adult outpatients at Lira Regional Referral Hospital (LRRH) in Northern Uganda. Employing a descriptive cross-sectional qualitative approach, data were collected from 100 adult patients aged 18 years and above attending the general outpatient department (OPD) at LRRH. Results revealed a substantial level of awareness of SCD among respondents, predominantly sourced from healthcare facilities and media outlets. While many recognized SCD as hereditary, misconceptions regarding its etiology and symptoms were evident. Notably, there was a knowledge gap regarding the treatability of SCD. Attitudes towards marrying individuals with SCD were predominantly negative, reflecting concerns about genetic transmission. However, there was a positive inclination towards premarital SCD testing. Regarding practices, reliance on medical facilities for SCD treatment was predominant, with minimal engagement with alternative therapies. Recommendations include sustained awareness campaigns, integration of SCD prevention and control initiatives, and further research to elucidate regional SCD prevalence determinants. Efforts to enhance male involvement in SCD advocacy and capacity building among healthcare providers are advocated to optimize SCD management and prevention strategies within the community. Keywords: Knowledge, Attitude, Practices, Sickle Cell Disease, Outpatients

Decline in Processing Speed Tells Only Half the Story: Developmental Delay in Children Living with Sickle Cell Disease.

Children with sickle cell disease (SCD) may experience cognitive difficulties, including slowed processing speed. Thus, we investigated if processing speed changes over time. From 1992-2001, 103 participants with SCD aged 3-16 years (n ≤ 8.99 = 45; n ≥ 9.00 = 58) completed cognitive assessments. MRI was available for 54 participants. Between 1992-2002, 58 participants consented to one or two further assessments. A repeated measures regression using linear mixed-effects modelling determined longitudinal changes in processing speed index (PSI), examining the interaction between age (continuous variable) and timepoint (i.e., assessment 1 or 3) and controlling for MRI infarct status (i.e., no infarct, silent infarct, or stroke). Those aged ≤8.99 and ≥9.00 at first assessment experienced PSI decline. Declines were most prominent for the processing speed coding subtest, with a significant interaction between timepoint and age, t(31) = 2.64, p = 0.01. This decline may reflect a developmental delay, likely due to disease progression, with slower improvements in processing speed. Although there have been significant improvements in SCD treatments, mostly in high-income countries, processing speed still remains a target; thus, incorporating clinical monitoring of processing speed may help identify delay and allow for early intervention.

Afro Medicinal Plants a Promising Remedy for Sickle Cell Anemia

Background: Sickle cell anemia is a disease that affects largely Africans and people in the tropics. It affects an average of 7.74 million and the mortality rate was 376,000 in the year 2021. Sickle cell disease was discovered in 1910 by a Famous scholar Herrick who described it as a hematological (Blood) disease and nearly three decades later, in 1949, Linus Pauling discovered the pathology of sickle cell anemia. Through molecular studies we further learned that sickle cell disease is caused by certain abnormalities in the hemoglobin of the patient, which costs millions of lives, plant products offer hope.&#x0D; Aims: The objectives were to determine the plants that are in use and the consensus clinical evidence about the plants and sickle cell diseases treatment. To provide easy access to consensus evidence to busy healthcare professionals and to educate the public.&#x0D; Place and Duration of Study: Department of Public Health, College of Health Science, Walden University, Minneapolis, USA, between July 2022 and October 2023.&#x0D; Methodology: A systematic review supported by a community approach to intervention services and native medicine theories supported the study. Search engines were Safari, Google, Google scholar, and Firefox.&#x0D; Results: Showed that while there were various approaches adopted by modern medicine to provide palliative care for persons with sickle cell diseases, which were directed at raising depleting nutrients, preventing infections and delaying the gelling point of the erythrocyte, no significant achievement has been made at reducing the disease and treating it effectively. Also, over 80% of the patients cannot afford the cost of the treatment. Thankfully, phytochemical compounds isolated from some medicinal plants- Carica papaya, Piper guineense, Cajanus cajan, Zanthoxylum zanthoxyloides, Terminalia catappa L, and formulations made from them such as Niprisan and Ciklavit, which have been approved for use for treating sickle cell diseases stands to be sustainable and efficacious offer hope. Outcome will bring a significant social change in local and global public health and economic activities.&#x0D; Conclusion: Clinically tested phytochemical compositions of implicated plants, herbal preparations, and specific nutrients investigated in this study possess anti-sickling properties and a couple of the preparations have been approved for sickle cell disease treatment in Nigeria.

The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment.

The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.

Endline assessment of knowledge about sickle cell disease among the tribal community of Chhotaudepur district of Gujarat.

Sickle cell disease (SCD) is a significant public health concern in India, with one of the highest disability burdens worldwide. For the success of the disease prevention and control program that aims to reduce prevalence through health promotion and screening, the public's prior knowledge of the disease is important. Hence, this study was conducted to assess baseline knowledge of the disease and effects of health education and community mobilization program in the SCD endemic tribal community of Gujarat. This quasi-experimental study was conducted in three phases at Chhotaudepur district of Gujarat, India. Knowledge of the community was assessed through the administration of pretested quantitative questionnaire in 1646 and 1631 individuals respectively during formative and evaluation phases. Differences between the proportions of two phases were statistically assessed by chi-square tests. Despite 75.3% of respondents having heard of SCD before, only 20% could perceive the correct cause. It was improved by 42% post-intervention. During the evaluation, 83% respondents recognized the most common symptom of extreme pain, whereas 86.8% identified the correct diagnostic method. Seventy-seven percent respondents reported modern medicine as a treatment for SCD at endline. Knowledge and awareness about SCD were found inadequate in the community. However, health education intervention strategies effectively improved knowledge related to the disease and its causes, diagnosis, and treatment. Hence, urgent action is required to incorporate community mobilization and awareness generation strategies to mitigate the disease burden.

Computer vision-enhanced microfluidic assay for evaluating the anti-sickling efficacy of sickle cell disease treatments

Computer vision-enhanced microfluidic assay for evaluating the anti-sickling efficacy of sickle cell disease treatments

Casgevy and Lyfgenia: Two gene therapies for sickle cell disease.

Two cell-based gene therapies – exagamglogene autotemcel (Casgevy – Vertex) and lovotibeglogene autotemcel (Lyfgenia – Bluebird Bio) – have been approved by the FDA for treatment of sickle cell disease in patients ≥12 years old with recurrent vaso-occlusive crises. They are the first gene therapies to be approved in the US for use in sickle cell disease; Casgevy is the first treatment to be approved in the US that uses CRISPR/Cas9 gene-editing technology.

Beyond the promise: evaluating and mitigating off-target effects in CRISPR gene editing for safer therapeutics.

Over the last decade, CRISPR has revolutionized drug development due to its potential to cure genetic diseases that currently do not have any treatment. CRISPR was adapted from bacteria for gene editing in human cells in 2012 and, remarkably, only 11years later has seen it's very first approval as a medicine for the treatment of sickle cell disease and transfusion-dependent beta-thalassemia. However, the application of CRISPR systems is associated with unintended off-target and on-target alterations (including small indels, and structural variations such as translocations, inversions and large deletions), which are a source of risk for patients and a vital concern for the development of safe therapies. In recent years, a wide range of methods has been developed to detect unwanted effects of CRISPR-Cas nuclease activity. In this review, we summarize the different methods for off-target assessment, discuss their strengths and limitations, and highlight strategies to improve the safety of CRISPR systems. Finally, we discuss their relevance and application for the pre-clinical risk assessment of CRISPR therapeutics within the current regulatory context.

Exagamglogene Autotemcel: First Approval.

Exagamglogene autotemcel (Casgevy™) is a genetically modified autologous CD34+ cell enriched population. It contains human haematopoietic stem and progenitor cells edited ex vivo by CRISPR/Cas9 (a DNA double strand break-inducing nuclease system) to differentiate into erythroid cells that produce high levels of foetal hemoglobin. Developed by Vertex Pharmaceuticals and CRISPR Therapeutics, exagamglogene autotemcel received its first approval on 16 November 2023 in the UK for the treatment of transfusion-dependent β-thalassemia (TDT) in patients aged ≥ 12years for whom haematopoietic stem cell (HSC) transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. On the same day, it was also approved in the UK for the treatment of sickle cell disease (SCD) in patients aged ≥ 12years with recurrent vasoocclusive crises (VOCs) who have the βS/βS, βS/β+ or βS/β0 genotype for whom HSC transplantation is appropriate and a human leukocyte antigen matched related HSC donor is not available. Subsequently, exagamglogene autotemcel was approved in the USA on 8 December 2023 for the treatment of SCD in patients aged ≥ 12years with recurrent VOCs and received a positive opinion in the EU on 14 December 2023 for the treatment of TDT and SCD. A regulatory assessment of exagamglogene autotemcel is currently underway for the treatment of TDT in the USA. This article summarizes the milestones in the development of exagamglogene autotemcel leading to these first approvals.

Treatment of sickle cell anemia using CRISPR and prime editing

Sickle cell disease is a hereditary blood disease caused by an invisible genetic mutation on the autosome, caused by a transversion mutation in which the 6th amino acid of the -peptide chain, glutamate, is replaced by valine, resulting in the formation of sickle hemoglobin, instead of normal hemoglobin. Due to genetic mutations leading to structural abnormalities in hemoglobin and morphological changes in red blood cells, red blood cells lose their deformability in hypoxic environments, leading to vascular blockage, causing severe pain and partial tissue ischemia in patients. Oxygen needs to be transported to various parts of the body through red blood cells, thereby affecting the transportation of oxygen in the body. In general, red blood cells are circular and elastic, making them easy to move in blood vessels. However, in sickle cells, these red blood cells are compressed and deformed, causing the transportation of oxygen in the blood to become stiff and viscous, potentially slowing or blocking blood flow. The most common complication of SCA is blockage of blood vessels, which leads to pain. Although this is a complex phenomenon, HbS aggregation is a fundamental pathological physiological phenomenon in SCA. HbS aggregation can lead to malignant changes in the shape and physical properties of red blood cells, leading to hemolytic anemia and preventing blood flow, especially in small blood vessels, which may damage some organs. Clinical manifestations include anemia, immunodeficiency, multiple organ damage, severe acute and chronic pain, and premature death. The quality of life of the patients was seriously affected.

Quantitative Model-Based Assessment of Multiple Sickle Cell Disease Therapeutic Approaches Alone and in Combination.

Three sickle cell disease (SCD) treatment strategies, stabilizing oxygenated hemoglobin (oxyHb), lowering 2,3-BPG, and inducing fetal hemoglobin (HbF) expression aim to prevent red blood cell (RBC) sickling by reducing tense-state sickle hemoglobin that contributes to polymer formation. Induction of 30% HbF is seen as the gold standard because 30% endogenous expression is associated with a lack of symptoms. However, the level of intervention required to achieve equivalent polymerization protection by the other strategies is uncertain, and there is little understanding of how these approaches could work in combination. We sought to develop an oxygen saturation model that could assess polymerization protection of all three approaches alone or in combination by extending the Monod-Wymann-Changeux model to include additional mechanisms. Applying the model to monotherapies suggests 51% sickle hemoglobin (HbS) occupancy with an oxyHb stabilizer or lowering RBC 2,3 BPG concentrations to 1.8 mM would produce comparable polymerization protection as 30% HbF. The model predictions are consistent with observed clinical response to the oxyHb stabilizer voxelotor and the 2,3-BPG reducer etavopivat. The model also suggests combination therapy will have added benefit in the case of dose limitations, as is the case for voxelotor, which the model predicts could be combined with 20% HbF or 2,3-BPG reduction to 3.75 mM to reach equivalent protection as 30% HbF. The proposed model represents a unified framework that is useful in supporting decisions in preclinical and early clinical development and capable of evolving with clinical experience to gain new and increasingly confident insights into treatment strategies for SCD.

Adherence to Hydroxyurea and Patients' Perceptions of Sickle Cell Disease and Hydroxyurea: A Cross-Sectional Study.

Background and Objectives: Hydroxyurea is a crucial treatment for sickle cell disease (SCD), but some patients' adherence to it remains suboptimal. Understanding patients' perspectives on SCD and HU is essential for improving adherence. This study aimed to assess hydroxyurea adherence and patients' perceptions of SCD and hydroxyurea among SCD patients in the Jazan region of Saudi Arabia. Materials and Methods: This cross-sectional study collected data from 217 SCD patients using self-administered questionnaires from August 2022 to January 2023. The survey covered patient demographics, SCD consequences, and other clinical data. We used the Brief Illness Perception Questionnaire (B-IPQ) to measure patients' disease perception and the 8-item Morisky Medication Adherence Scale (MMAS-8) to evaluate patients' adherence to HU. Data were analysed using descriptive, t-test, and chi-square tests, and the p-value was set at <0.05 for significance. Results: More than half of the patients were male, with a mean age of 28.09 ± 8.40 years. About 57.6% of the patients were currently using HU. About 81.6% of HU users reported low adherence. The adherence was lower among individuals with infections/recurrent infections and in patients who received repeated blood transfusions. ICU admission, blood transfusion, and certain SCD complications were associated with HU use. Male patients had a higher perception of SCD consequences, concern, and understanding. ICU-admitted and recurrent hospitalized patients had a higher perception of the SCD-related consequences, symptoms, concerns, and emotional responses. Conclusions: HU seems a well-established and efficacious disease-modifying agent, but its underutilization for SCD patients remains challenging. To overcome the adherence challenges, healthcare providers must educate SCD patients about the role of hydroxyurea in lowering disease severity and addressing side effects to obtain maximum benefits. Healthcare providers may consider tailored educational interventions to improve adherence, particularly for patients with infections, recurrent hospitalizations, or repeated blood transfusions. Further research is needed to identify strategies for improving hydroxyurea adherence and patient education among SCD patients.

Evaluation the in vitro Anti-Sickle Cell Potential of Two Medicinal Plant Species, Rhynchospora corymbosa and Olax subscorpioïdea on the Inhibition of Falciformation of SS Genotype Erythrocytes

Aims: Sickle cell disease is one of the world's leading genetic disorders. It is characterized by the presence of an abnormal hemoglobin HbS in the blood. The anomaly affects the primary structure of hemoglobin, through the substitution of valine for glutamic acid. In traditional medicine, two plant species, Rhynchospora corymbosa and Olax subscorpioïdea, are used to treat this condition.&#x0D; Place and Duration of Study: Agro-valuation Laboratory, Hematology Clinic laboratory of Cocody Hospital University (CHU), between June-Aout 2021 and June-July 2022.&#x0D; Methodology: Following a triphytochemical test, the effect of each species on the in vitro inhibition of SS erythrocyte falciformation was evaluated.&#x0D; Results: Thus an abundance of alkaloids, tannins, saponins, polyterpenes and sterols were found in the families of molecules identified in Rhynchospora corymbosa. As for the decocted Olax subscorpioïdea, in addition to the families of molecules identified in Rhynchospora corymbosa the polyphenols, leuco-anthocyanins and flavonoids were found. In addition, at an equal concentration of 0.312 mg/mL, decoctions of Rhynchospora corymbosa and Olax subscorpioïdea gave an inhibition rates of 80 and 84 % respectively. Both extracts showed activity on in vitro falciformation inhibition. This activity is thought to be due to the presence of chemical groups with anti-oxidant and anti-inflammatory properties.&#x0D; Conclusion: The use of Rhynchospora corymbosa and Olax subscorpioïdea in the treatment of sickle cell disease in Côte d'Ivoire would be justified.