bims-sicedi 2024-12-29 papers

Cytotherapy. 2024 Dec 26. pii: S1465-3249(24)00925-3. [Epub ahead of print]

Gene therapy for sickle cell disease: recent advances, clinical trials and future directions.

Sickle cell disease (SCD) is the most common inherited blood disorder worldwide, impacting millions and imposing severe healthcare challenges, particularly in resource-limited regions. Current treatments have variable efficacy and require lifelong adherence. Allogeneic Hematopoietic Stem Cell Transplantation can be curative but comes with significant side effects and limited donor availability limits its widespread applicability. Gene therapy, by addressing the root genetic causes, offers a revolutionary alternative. This article discusses the molecular mechanisms of SCD and β-thalassemia and highlights advancements in gene therapy, such as gene addition via lentiviral vectors and gene editing with CRISPR/Cas9 technology. Clinical trials have brought about significant progress but challenges remain, including leukemogenesis, delivery efficiency and cost. Future efforts must focus on enhancing efficiency, reducing costs, developing nongenotoxic conditioning regimens and methods for in vivo application.

Keywords: CRISPR/Cas9 gene editing; Fetal hemoglobin (HbF) induction; Gene therapy; Hemoglobinopathies; Sickle cell disease; lentiviral vectors

DOI: https://doi.org/10.1016/j.jcyt.2024.11.006

Cureus. 2024 Nov;16(11): e74489

A Retrospective Analysis of Demographics, Clinical Features, and Treatment Patterns in Sickle Cell Disease Patients at a Tertiary Healthcare Centre of North East India.

Anupam Dutta, Taniya S Dutta, Amlin Shukla, Papori Gogoi.

Background Sickle cell disease (SCD) is a hereditary disorder marked by abnormal hemoglobin (HbS), leading to chronic hemolytic anemia, vaso-occlusive crises (VOCs), and multi-organ complications. In India, the prevalence of SCD is highest among tribal populations in states like Madhya Pradesh, Maharashtra, Odisha, and Assam, with the disease burden exacerbated by limited healthcare access, especially in rural regions. This study provides a comprehensive analysis of the demographic profile, clinical features, and treatment patterns of SCD patients at a tertiary healthcare center in Upper Assam, where the prevalence of SCD is high among the tea tribe communities. Methods This retrospective observational study included 250 patients diagnosed with various SCD subtypes who presented with SCD-related complications at Assam Medical College and Hospital between January 2020 and December 2023. Data were obtained from medical records in the departments of medicine and pediatrics, covering demographic variables (age, gender, ethnicity), clinical characteristics (complications, hemoglobin levels, genotype, history of hospitalizations), and treatment details (frequency and type of blood transfusions, use of hydroxyurea and chelating agents). Descriptive statistics summarized demographic and clinical features, while chi-square tests and t-tests were used for bivariate analysis. Logistic regression identified factors associated with high transfusion requirements. Results The study population had a mean age of 17.2 years, with 54.4% male predominance. Most patients (87%) had sickle cell anemia (HbSS), while the remainder had other genotypes including HbSA, HbSE, and sickle cell thalassemia. The most common presenting symptoms were fever (61.2%) and bone/joint pain (48.4%), indicative of VOCs and frequent infections. Pallor (30%) and abdominal pain (25.6%) were also prominent. Half of the patients (125) received hydroxyurea, though its uptake was limited by availability and cost. A high transfusion burden was noted, with 72.4% of patients requiring between five to 12 transfusions annually. However, only 22.4% received chelation therapy to manage iron overload, reflecting the cost constraints in accessing these agents. Laboratory findings indicated a mean hemoglobin level of 7.19 g/dL and elevated serum ferritin levels due to repeated transfusions. The frequency of blood transfusions was higher compared to Western studies, emphasizing the need for more accessible disease-modifying therapies in resource-limited settings. Conclusions The findings of this study illustrate the significant clinical and transfusion burden experienced by SCD patients in Upper Assam. This population relies heavily on blood transfusions due to limited access to hydroxyurea and other advanced therapies. The study underscores a critical need for improved access to hydroxyurea, expanded availability of chelation therapy, and greater healthcare support for managing SCD-related complications in resource-limited settings. As India's National Sickle Cell Anemia Elimination Mission is implemented, regional studies such as this are essential for tailoring public health interventions to meet the specific needs of high-prevalence areas, especially among underserved tribal communities.

Keywords: clinical features; hospital epidemiology; hydroxyurea therapy; north east region of india; sickle cell anaemia; sickle cell disease complications; sickle cell disease: scd

DOI: https://doi.org/10.7759/cureus.74489

Br J Haematol. 2024 Dec 22.

Sickle cell anaemia therapy in 2025.

Alan N Schechter.

New pharmacological therapies for sickle cell anaemia have not been as efficacious as hoped, while widespread application of curative stem cell and gene therapies is not likely to occur soon. This situation raises the question about whether more attention now be devoted to the use of hydroxyurea in this disease.

Keywords: fetal haemoglobin; hydroxyurea; sickle cell anaemia; therapy

DOI: https://doi.org/10.1111/bjh.19933

Health Care Transit. 2024 ;2 100056

Initial outcomes in a sickle cell disease transition clinic.

Katheryne Madrazo-Aguirre, Jean-Antoine Ribeil, Amy E Sobota.

Background: Transition in sickle cell disease (SCD) is associated with an alarming increase in acute care utilization, cost, and risk of early mortality. Effective transition preparation is crucial to address these issues. We established a multidisciplinary transition clinic at our urban SCD center in the fall of 2021. At each visit patients were introduced to the transition process and met with a pediatric and adult SCD provider.
Methods: We reviewed charts of patients attending the clinic from September 2021 to May 2023. Data were collected on the number of visits in the transition and adult SCD clinics. Clinic notes were reviewed, identifying the main topics of discussion, and examining patient attitudes and feelings towards transition.
Results: Twenty-two patients aged 20-27 years with 35 total visits were included in the analysis. Eighteen (82%) patients had at least 1 visit to transition clinic. Out of 10 scheduled patients, 8 attended their first adult care visit within 2.4 months of their last transition visit. Medical topics brought up by patients included difficulty remembering to take hydroxyurea, questions about reproductive and menstrual health, and support pursing higher education with a chronic disease. Patients expressed a variety of feelings about transition from "no concerns" to "nervousness" and questioning "what to expect". Concerns were alleviated by learning about the process. One patient reported feeling "much better" after being introduced to the adult provider.
Conclusion: We demonstrated that a collaborative transition clinic prepares young adults with SCD for transition to adult care. Meeting with their adult SCD provider prior to transfer helped alleviate patients' concerns. Future work will involve tracking patients as they integrate into adult clinic.

Keywords: Clinic; Sickle cell disease; Transition

DOI: https://doi.org/10.1016/j.hctj.2024.100056

Lancet Infect Dis. 2024 Dec 20. pii: S1473-3099(24)00737-0. [Epub ahead of print]

Weekly dihydroartemisinin-piperaquine versus monthly sulfadoxine-pyrimethamine for malaria chemoprevention in children with sickle cell anaemia in Uganda and Malawi (CHEMCHA): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: In many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine-pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin-piperaquine and monthly sulfadoxine-pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine-pyrimethamine resistance of P falciparum in Uganda and Malawi.
METHODS: We did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin-piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine-pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099.
FINDINGS: Between April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin-piperaquine group and 357 participants in the sulfadoxine-pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2-18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin-piperaquine group and 43.7 events per 100 person-years in the sulfadoxine-pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14-0·30], p<0·0001). The incidence of hospitalisation with any malaria was lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (10·4 vs 37·0 events per 100 person-years; IRR 0·29 [0·20-0·42], p<0·0001) and the number of blood transfusions was also lower in the dihydroartemisinin-piperaquine group than the sulfadoxine-pyrimethamine group (52·1 vs 72·5 events per 100 person-years; IRR 0·70 [0·54-0·90], p=0·006). The incidence of all-cause unscheduled clinic visits and all-cause hospitalisations were similar between the two groups, however, participants in the dihydroartemisinin-piperaquine group had more clinic visits unrelated to malaria (IRR 1·12 [1·00-1·24], p=0·042) and more hospitalisations with lower respiratory tract events (16·5 vs 8·5 events per 100 person-years; IRR 1·99 [1·25-3·16], p=0·0036) than participants in the sulfadoxine-pyrimethamine group. The number of serious adverse events in the dihydroartemisinin-piperaquine group was similar to that in the sulfadoxine-pyrimethamine group (vaso-occlusive crisis [154 of 367 participants dihydroartemisinin-piperaquine group vs 132 of 357 participants in the sulfadoxine-pyrimethamine group] and suspected sepsis [115 participants vs 92 participants]), with the exception of acute chest syndrome or pneumonia (51 participants vs 32 participants). The number of deaths were similar between groups (six [2%] of 367 participants in the dihydroartemisinin-piperaquine group and eight (2%) of 357 participants in the sulfadoxine-pyrimethamine group).
INTERPRETATION: Malaria chemoprophylaxis with weekly dihydroartemisinin-piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine-pyrimethamine. However, monthly sulfadoxine-pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin-piperaquine should be considered as an alternative to sulfadoxine-pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years.
FUNDING: Research Council of Norway and UK Medical Research Council.
TRANSLATIONS: For the Chichewa, Acholi, Lusoga and Luganda translations of the abstract see Supplementary Materials section.

DOI: https://doi.org/10.1016/S1473-3099(24)00737-0

Blood Genom Discov. 2025 ;pii: 10001. [Epub ahead of print]9(1):

Alterations of T Cell Subsets Associated with Sickle Cell Trait.

Alexander P Reiner, Laura M Raffield, Lynette Ekunwe, Nels C Olson, Paul L Auer, Margaret F Doyle.

Sickle cell trait (SCT) has been associated with alterations in various immune-related laboratory parameters including lower circulating lymphocyte counts. To further characterize the impact of SCT on the immune system, we performed flow cytometry of monocyte and lymphocyte immune cell subsets from peripheral blood mononuclear cells collected in a large, community-based cohort of SCT-positive (n = 68) and SCT-negative (n = 959) Black adults. SCT was significantly associated with lower proportions of CD8+ and CD4+ T cell subsets that include senescent-like markers of repeated immune system challenges. These immune alterations could have potential implications for the susceptibility of individuals with SCT to various infectious diseases.

Keywords: CD4; CD8; Flow Cytometry; Sickle Cell; T Lymphocyte

DOI: https://doi.org/10.70322/bgd.2025.10001