bims-sicedi 2024-11-10 papers

bims-sicedi

Biomed News

on Sickle cell disease

Issue of 2024–11–10
eleven papers selected by
João Conrado Khouri dos Santos, Universidade de São Paulo

History, Advances, and Challenges of Sickle Cell Disease Treatment.
Therapeutic potential of the latest oxygen affinity-modifying agent, GBT021601, for treating sickle cell disease is questionable.
Introducing a G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.
Editor's Note to the letter 'Therapeutic potential of the latest oxygen affinity modifying agent, GBT021601, for treating sickle cell disease is questionable' by Drs. Eaton, Alaimo, Metaferia, Cellmer, Thein and Bunn.
Cyclosporin H Improves the Transduction of CD34+ Cells with an Anti-Sickling Globin Vector, a Possible Therapeutic Approach for Sickle Cell Disease.
Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease.
Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease: final results from the phase II SOLACE-adults study.
Late effects of hemopoietic stem cell transplant for sickle cell disease: monitoring and management.
Longitudinal outcomes of chronically transfused adults with sickle cell disease and a history of childhood stroke.
Memantine treatment in sickle cell disease: A 1-year study of its effects on cognitive functions and neural processing.
Ultrasonographic assessment of spleen size and pattern of change among sickle cell disease patients and healthy controls in North-Eastern Nigeria.

Clin Lab Med. 2024 Dec;pii: S0272-2712(24)00043-X. [Epub ahead of print]44(4): 679-691

History, Advances, and Challenges of Sickle Cell Disease Treatment.

Ritika Walia, Kleber Y Fertrin, Daniel E Sabath.

  Sickle cell disease (SCD) is marked by red blood cells that deform into a sickle shape, causing severe health complications. Historic neglect and slow therapeutic progress have left many, especially African descendants, vulnerable. Recent treatment strides include novel drugs and gene therapy, promising improved management. Nonetheless, challenges persist with treatment adoption because of cost, adverse effects, and accessibility. Advancements hold hope for enhanced life quality and longevity for SCD patients.

Keywords:  Health equity; Racism; Sickle cell; Treatment advances

DOI:  https://doi.org/10.1016/j.cll.2024.07.004
Br J Haematol. 2024 Nov 06.

Therapeutic potential of the latest oxygen affinity-modifying agent, GBT021601, for treating sickle cell disease is questionable.

Braydon Alaimo, Belhu Metaferia, Troy Cellmer, Swee Lay Thein, H Franklin Bunn, William A Eaton.

DOI: https://doi.org/10.1111/bjh.19697
Mol Ther. 2024 Oct 25. pii: S1525-0016(24)00678-6. [Epub ahead of print]

Introducing a G-Makassar variant in HSCs by in vivo base editing treats sickle cell disease in mice.

Chang Li, Aphrodite Georgakopoulou, Kiriaki Paschoudi, Anna K Anderson, Lishan Huang, Sucheol Gil, Maria Giannaki, Efthymia Vlachaki, Gregory A Newby, David R Liu, Evangelia Yannaki, Hans-Peter Kiem, André Lieber.

Precise repair of the pathogenic mutation in hematopoietic stem cells (HSCs) represents an ideal cure for patients with sickle cell disease (SCD). Here, we demonstrated correction of the SCD phenotype by converting the sickle mutation codon (GTG) into a benign G-Makassar variant (GCG) using in vivo base editing in HSCs. We demonstrated successful production of helper-dependent adenoviral vectors expressing an all-in-one base editor mapping to the sickle mutation site. In HSC-enriched cells from SCD patients, transduction with the base editing vector in vitro resulted in 35% GTG > GCG conversion and phenotypic improvements of derived red blood cells. After ex vivo transduction of HSCs from a SCD mouse model and subsequent transplantation, we achieved an average of 88% editing at the target site in transplanted mice. Importantly, in vivo HSC base editing followed by selection generated 24.5% Makassar variant in long-term repopulating HSCs of SCD mice. The treated animals demonstrated correction of disease hallmarks without showing noticeable side effects. Off-target analyses at top-scored genomic sites revealed no off-target editing. This in vivo approach requires only one non-integrating vector, only intravenous/subcutaneous injections, and minimal in vivo selection. This technically simple approach has the potential for scalable applications in resource-limiting regions where SCD is prevalent.

DOI: https://doi.org/10.1016/j.ymthe.2024.10.018
Br J Haematol. 2024 Nov 06.

Editor's Note to the letter 'Therapeutic potential of the latest oxygen affinity modifying agent, GBT021601, for treating sickle cell disease is questionable' by Drs. Eaton, Alaimo, Metaferia, Cellmer, Thein and Bunn.

Peter Hokland.



Keywords:  haemoglobinopathies; sickle cell anaemia; therapy

DOI:  https://doi.org/10.1111/bjh.19865
Hum Gene Ther. 2024 Nov 06.

Cyclosporin H Improves the Transduction of CD34+ Cells with an Anti-Sickling Globin Vector, a Possible Therapeutic Approach for Sickle Cell Disease.

Mirella Mormin, Luc Rigonnot, Anne Chalumeau, Annarita Miccio, Clémence Fournier, Sandya Pajanissamy, Marie Dewannieux, Anne Galy.

  Sickle cell disease (SCD) is a debilitating monogenic disease originating from mutations in the hemoglobin beta chain gene producing an abnormal hemoglobin HbS. The polymerization of HbS is responsible for the sickling of erythrocytes leading to anemia and vaso-occlusive events. Gene therapy is a promising treatment of SCD, and two different gene therapy drugs, using gene editing or gene transfer, have already reached the marketing stage. There is still a need to improve the efficacy of gene therapy in SCD, particularly when using anti-sickling beta-globin gene transfer strategies, which must outcompete the pathological HbS. One possibility is to increase transduction by inhibiting lentiviral restriction factors such as interferon-induced transmembrane proteins (IFITMs). This can be achieved by the addition of cyclosporin H (CsH) during the transduction process. This strategy was applied here in CD34+ hematopoietic progenitor and stem cells obtained from cord blood (CB). A first series of experiments with lentiviral vector coding for a green fluorescent protein (GFP) gene confirmed that the addition of CsH enhanced transgene expression levels and vector copy number per cell (VCN), while CD34+ cells remained viable and functional. Notably, the production of colony-forming cells (CFC) remained unaffected unless very high VCN values were reached. In a second step, CD34+ cells obtained from the CB of newborns with homozygous (n = 2) or heterozygous (n = 1) SCD mutations were transduced with the GLOBE-AS3 lentiviral vector coding for the HbAS3 anti-sickling beta globin. As with GFP, GLOBE-AS3 lentiviral transduction was clearly enhanced by CsH, leading to VCN > 2 and therapeutic levels of expression of the HbAS3. Moreover, the process did not affect the viability or functions of CFC. The combination of CB progenitors, the GLOBE-AS3 vector, and CsH is thus shown here to be a promising approach for the treatment of SCD.

Keywords:  cyclosporin H; gene therapy; hematopoietic stem and progenitor cells; lentiviral vectors; sickle cell disease; transduction enhancer

DOI:  https://doi.org/10.1089/hum.2024.098
PLoS One. 2024 ;19(11): e0307049

Identification of small molecule agonists of fetal hemoglobin expression for the treatment of sickle cell disease.

Jian-Ping Yang, Rachel Toughiri, Anshu P Gounder, Dan Scheibe, Matt Petrus, Sarah J Fink, Sebastien Vallee, Jon Kenniston, Nikolaos Papaioannou, Steve Langston, Narender R Gavva, Shane R Horman.

Induction of fetal hemoglobin (HbF) has been shown to be a viable therapeutic approach to treating sickle cell disease and potentially other β-hemoglobinopathies. To identify targets and target-modulating small molecules that enhance HbF expression, we engineered a human umbilical-derived erythroid progenitor reporter cell line (HUDEP2_HBG1_HiBiT) by genetically tagging a HiBiT peptide to the carboxyl (C)-terminus of the endogenous HBG1 gene locus, which codes for γ-globin protein, a component of HbF. Employing this reporter cell line, we performed a chemogenomic screen of approximately 5000 compounds annotated with known targets or mechanisms that have achieved clinical stage or approval by the US Food and Drug Administration (FDA). Among them, 10 compounds were confirmed for their ability to induce HbF in the HUDEP2 cell line. These include several known HbF inducers, such as pomalidomide, lenalidomide, decitabine, idoxuridine, and azacytidine, which validate the translational nature of this screening platform. We identified avadomide, autophinib, triciribine, and R574 as novel HbF inducers from these screens. We orthogonally confirmed HbF induction activities of the top hits in both parental HUDEP2 cells as well as in human primary CD34+ hematopoietic stem and progenitor cells (HSPCs). Further, we demonstrated that pomalidomide and avadomide, but not idoxuridine, induced HbF expression through downregulation of several transcriptional repressors such as BCL11A, ZBTB7A, and IKZF1. These studies demonstrate a robust phenotypic screening workflow that can be applied to large-scale small molecule profiling campaigns for the discovery of targets and pathways, as well as novel therapeutics for sickle cell disease and other β-hemoglobinopathies.

DOI: https://doi.org/10.1371/journal.pone.0307049
Ther Adv Hematol. 2024 ;15 20406207241292508

Pharmacokinetics, pharmacodynamics, safety, and efficacy of crizanlizumab in patients with sickle cell disease: final results from the phase II SOLACE-adults study.

Julie Kanter, Sarah Mennito, Santosh M Nair, Deepa Manwani, Abdullah Kutlar, Nirmish Shah, Deborah Keefe, Hariprasad Madhamshetty, Michele Nassin, Evgeniya Reshetnyak, Anisha E Mendonza, Darla Liles.

   Background: Crizanlizumab is a novel inhibitor of P-selectin, a key player in multicellular adhesion and inflammatory signaling, that leads to vaso-occlusion in sickle cell disease (SCD).
Objectives: The SOLACE-adults study evaluated the pharmacokinetics, pharmacodynamics (P-selectin inhibition), safety, and efficacy of crizanlizumab, with or without hydroxyurea/hydroxycarbamide, in patients with SCD.
Design: Phase II, single-arm, multicenter study.
Methods: Patients with SCD aged 16-70 years, with ⩾1 vaso-occlusive crisis (VOC) within 12 months before screening, received crizanlizumab 5.0 or 7.5 mg/kg intravenous infusion every 4 weeks; dose groups were enrolled sequentially.
Results: Of 57 patients enrolled, 45 received crizanlizumab 5.0 mg/kg and 12 received 7.5 mg/kg for a median duration of 206 and 170 weeks, respectively. Crizanlizumab concentrations reached maximum levels after a 30-min infusion and remained steady for 6 h, without significant accumulation. P-selectin inhibition was nearly complete for both doses. The median (interquartile range) absolute change in the annualized rate of VOCs leading to healthcare visit from baseline was -0.79 (-3.04, 2.01) in the 5.0 mg/kg group and -0.98 (-1.11, -0.41) in the 7.5 mg/kg group. All patients experienced at least one adverse event (AE), with no apparent differences between the two doses in the frequency and severity of AEs. Grade ⩾3 AEs occurred in 60% of the 5.0 mg/kg group and 58% of the 7.5 mg/kg group. Two patients in the 5.0 mg/kg group and one in the 7.5 mg/kg group had severe crizanlizumab-related infusion-related reactions, which resolved with treatment. No patients developed antibodies against crizanlizumab.
Conclusion: Crizanlizumab 5.0 and 7.5 mg/kg demonstrated a dose-proportional increase in exposure, sustained P-selectin inhibition, a tolerable safety profile, and a sustained reduction in VOCs leading to healthcare visit. This suggests that crizanlizumab is a useful treatment option for patients with SCD who have experienced VOCs.
Trial Registration: NCT03264989.

Keywords:  crizanlizumab; pharmacodynamics; pharmacokinetics; sickle cell disease; vaso-occlusive crises

DOI:  https://doi.org/10.1177/20406207241292508
Expert Rev Hematol. 2024 Nov 05. 1-15

Late effects of hemopoietic stem cell transplant for sickle cell disease: monitoring and management.

Marti Goldenberg, Sophie Lanzkron, Lydia H Pecker.

   INTRODUCTION: Allogeneic hemopoietic stem cell transplantation (HSCT) is a curative therapy for sickle cell disease (SCD). Exposure to both SCD and HSCT conditioning regimens is associated with late health effects.
AREAS COVERED: This review addresses post-HSCT outcomes and late health effects among individuals with SCD exposed to allogeneic HSCT regimens, summarizes recommendations for long-term care, and identifies future survivorship research needs.
EXPERT OPINION: Individuals with SCD exposed to HSCT and gene therapy require multidisciplinary care to monitor late health effects. To optimize care, multi-disciplinary clinics that include experts in late effects of HSCT exposure, SCD, complex chronic pain, mental health, and social work are needed. Research defining the late effects of exposure is needed to inform patient management and build clinical care infrastructure.

Keywords:  Curative therapy; hemopoietic stem cell transplant; late effects; sickle cell disease; survivorship challenges

DOI:  https://doi.org/10.1080/17474086.2024.2423368
Transfusion. 2024 Nov 05.

Longitudinal outcomes of chronically transfused adults with sickle cell disease and a history of childhood stroke.

Jennifer M Jones, Julia Wool, Elizabeth P Crowe, Evan M Bloch, Lydia H Pecker, Sophie Lanzkron.

   BACKGROUND: Many children with sickle cell disease (SCD) who suffer a stroke receive chronic transfusion therapy (CTT) indefinitely; however, their adulthood neurologic outcomes have not been reported. Understanding these outcomes is critical to inform decisions regarding curative therapy in childhood.
STUDY DESIGN AND METHODS: In this retrospective study, we described a cohort of adults with SCD and a history of childhood stroke who received care at a single center and compared their outcomes with matched subjects without childhood stroke using chi2 and Mann-Whitney U tests.
RESULTS: Of 42 subjects with childhood stroke, all received CTT for secondary stroke prophylaxis. Five (11%) developed recurrent stroke. The rate of stroke was similar in subjects with and without childhood stroke (0.7 vs. 1.1 per 100 person·years, p = .63). Both cohorts exhibited evidence of iron overload (median ferritin 2227 vs. 1409 ng/dL, p = .10) and alloimmunization (45% vs. 45%, p = 1.0), despite receiving care in a comprehensive SCD program.
DISCUSSION: For adults with SCD who had a childhood stroke, our results suggest CTT returns the risk of stroke to that of age-matched stroke naïve patients with SCD.

Keywords:  cerebrovascular accident; chronic red cell exchange transfusions; sickle cell disease; therapeutic apheresis

DOI:  https://doi.org/10.1111/trf.18041
Br J Haematol. 2024 Nov 05.

Memantine treatment in sickle cell disease: A 1-year study of its effects on cognitive functions and neural processing.

Sivan Raz, Ariel Koren, Anna Yu Bogdanova, Max Gassmann, Carina Levin.

  This study evaluates the neurocognitive and electrophysiological effects of 1-year memantine treatment in 14 adolescents and young adults (mean age 24 years) with sickle cell disease (SCD, incluing sickle cell anaemia and sickle cell β-thalassemia), hypothesizing improvements in cognitive functions and neural processing. Participants underwent assessments using subtests from the Wechsler Intelligence Scale and a computerized task-switching paradigm with concurrent event-related potential (ERP) recordings, both before and after the treatment period. Assessments focused on processing speed, working memory, attention and executive function. ERP measurements targeted brain response changes during task switching. Memantine treatment enhanced cognitive test performance, especially in processing speed as shown by the Digit-Symbol Coding and Symbol-Search tests. Results indicated improved visuospatial and graphomotor speed, working memory and attention. The task-switching test revealed reduced error rates, suggesting decreased cognitive load and enhanced executive control. Electrophysiological changes in P1 and P3 amplitudes at frontal and parietal locations post-treatment pointed to more efficient neural processing in tasks requiring cognitive flexibility. These preliminary findings from a Phase II clinical study serve as a 'proof of concept', exploring the feasibility and potential effectiveness of memantine treatment in SCD-a previously uninvestigated context. They support the rationale for more extensive investigations to confirm these results and assess memantine's broader effectiveness.

Keywords:  cognitive function; event‐related potentials; memantine; sickle cell disease

DOI:  https://doi.org/10.1111/bjh.19866
Ultrasound. 2024 Nov;32(4): 260-269

Ultrasonographic assessment of spleen size and pattern of change among sickle cell disease patients and healthy controls in North-Eastern Nigeria.

Adama Isah Ladu, Caroline Jeffery, Abubakar Farate, Abubakar G Farouk, Fatima M Abulfathi, Adekunle Adekile, Imelda Bates.

   Background: Ultrasonography is an established and reliable method for assessing the spleen. Because of variation due to genetic and other environmental factors including malaria endemicity, interpretation of spleen sizes requires a knowledge of the normal reference range for a given population. This study aimed to identify spleen size reference ranges across age groups of healthy controls to serve as a baseline to assess changes in spleen size in patients with sickle cell disease.
Methods: Using a cross-sectional study design, spleen size was measured in healthy people of different age groups and steady-state sickle cell disease patients (children and adults) using abdominal ultrasonography. Using the age-group-specific reference values obtained from the controls, spleens were classified into small, normal size or enlarged among the sickle cell disease patients.
Results: The study consisted of 109 (34.8%) healthy controls and 204 (65.2%) steady-state sickle cell disease patients. The spleen was visualised in all the controls (n = 109) and in 107 (52.4%) sickle cell disease patients. Using cut-off values for spleen length among the controls across age groups (< 5 years (5.0-7.0 cm); 5-9 years (5.5-8.5 cm); 10-14 years (6.0-11.0 cm) and ⩾ 15 years (7.0-12.5 cm)), spleen size was classified as small (n = 18/204; 8.87%), normal (n = 68/204; 33.3%) and enlarged (n = 21/204; 10.3%) among the sickle cell disease patients.
Conclusion: Model-based age-group reference ranges and percentile curves for splenic dimensions based on ultrasonography among normal controls in North-Eastern Nigeria were established and may be of value in assessing spleen sizes among sickle cell disease patients living in malaria-endemic regions of Africa.

Keywords:  Nigeria; Ultrasound; reference ranges; sickle cell disease; spleen

DOI:  https://doi.org/10.1177/1742271X241241778