Gene editing is a growing gene engineering technique that allows accurate editing of a broad spectrum of gene-regulated diseases to achieve curative treatment and also has the potential to be used as an adjunct to the conventional treatment of diseases. Gene editing technology, mainly based on clustered regularly interspaced palindromic repeats (CRISPR)-CRISPR-associated protein systems, which is capable of generating genetic modifications in somatic cells, provides a promising new strategy for gene therapy for a wide range of human diseases. Currently, gene editing technology shows great application prospects in a variety of human diseases, not only in therapeutic potential but also in the construction of animal models of human diseases. This paper describes the application of gene editing technology in hematological diseases, solid tumors, immune disorders, ophthalmological diseases, and metabolic diseases; focuses on the therapeutic strategies of gene editing technology in sickle cell disease; provides an overview of the role of gene editing technology in the construction of animal models of human diseases; and discusses the limitations of gene editing technology in the treatment of diseases, which is intended to provide an important reference for the applications of gene editing technology in the human disease.

Red blood cell (RBC) aging manifests through progressive changes in cell morphology, rigidity, and expression of membrane proteins. To maintain the quality of circulating blood, splenic macrophages detect the biochemical signals and biophysical changes of RBCs and selectively clear them through erythrophagocytosis. In sickle cell disease (SCD), RBCs display alterations affecting their interaction with macrophages, leading to aberrant phagocytosis that may cause life-threatening spleen sequestration crises. To illuminate the mechanistic control of RBC engulfment by macrophages in SCD, we integrate a system biology model of RBC-macrophage signaling interactions with a biophysical model of macrophage engulfment, as well as in vitro phagocytosis experiments using the spleen-on-a-chip technology. Our modeling framework accurately predicts the phagocytosis dynamics of RBCs under different disease conditions, reveals patterns distinguishing normal and sickle RBCs, and identifies molecular targets including Src homology 2 domain-containing protein tyrosine phosphatase-1 (SHP1) and cluster of differentiation 47 (CD47)/signal regulatory protein α (SIRPα) as therapeutic targets to facilitate the controlled clearance of sickle RBCs in the spleen.

Inherited anemia continues to pose a significant public health concern on a global scale, owing to its extensive geographical prevalence, substantial patient population, and profound ramifications. Here, we investigated detailed information on inherited anemias (including thalassemias, thalassemias trait, sickle cell disease, sickle cell trait, G6PD deficiency, and G6PD trait) for the period 1990-2019 from the Global Burden of Disease study. Over the course of three decades, there has been a persistent rise in the incidence of inherited anemias worldwide, culminating in a total of 44,896,026 incident cases in 2019. However, the prevalence of inherited anemias has exhibited a consistent downward trend over successive years. Significantly, these inherited anemias primarily impact females, exhibiting a male-to-female ratio of 1:1.88. Among males, the most prevalent inherited anemia is G6PD deficiency, whereas G6PD trait prevails among females. The incidence rates of inherited anemias and their temporal trend exhibited significant variations across different regions, with Central Sub-Saharan Africa displaying the highest incidence rates and Central Latin America experiencing the most substantial decline. The findings of this study suggest a significant correlation between the Socio-Demographic index (SDI) and incidence rates of inherited anemias, particularly in regions with lower SDI levels such as Africa and South Asia. These results contribute valuable insights for the analysis of global trends in the burden of inherited anemias.

The aim is to elucidate the relationship between sickle cell disorder and severe COVID-19. We systematically searched the required articles in three electronic databases, extracting and pooling effect sizes (ES) and 95% confidence interval (CI) from each eligible study to evaluate the effect of combined sickle cell disorder on adverse consequences in patients with COVID-19. This meta-analysis included 21 studies. Sickle cell disease (SCD) was a risk factor for mortality (pooled ES = 1.70, 95% CI: 1.00-2.92, p = 0.001), hospitalization (pooled ES = 6.21, 95% CI: 3.60-10.70, p = 0.000) and intensive care unit (ICU) admission (pooled ES = 2.29, 95% CI: 1.61-3.24, p = 0.099) in COVID-19 patients. Patients with SCD had an increased risk of respiratory failure/mechanical ventilation, but a statistical association was not found (pooled ES = 1.21, 95%CI: 0.74-1.98, p = 0.036). There was significant heterogeneity between SCD and death, hospitalization, and respiratory failure/mechanical ventilation. The results of meta-regression of SCD and hospitalization suggested that the tested variables including Area (p = 0.642), study design (p = 0.739), sample size (p = 0.397), proportion of males (p = 0.708), effect type (p = 0.723), whether confounding factors are adjusted (p = 0.606) might not be the source of heterogeneity. In addition, sickle cell trait (SCT) was significantly associated with the mortality (pooled ES = 1.54, 95% CI: 1.28-1.85, p = 0.771) and hospitalization (pooled ES = 1.20, 95% CI: 1.07-1.35，p = 0.519) in patients with COVID-19. But any increased risk of ICU admission/severe (pooled ES = 1.24, 95% CI: 0.95-1.62, p = 0.520) and mechanical ventilation (OR = 1.00, 95%CI:0.59-1.69) in COVID-19 patients with SCT was not observed. Sensitivity analysis demonstrated that the results were robust. The results of the funnel plot and Egger\'s test did not support the existence of publication bias. Current meta-analysis indicated that sickle cell disorder has a meaningful impact on COVID-19 progression to severe cases and associated deaths. However, further investigations and research to validate the current findings is indispensable.

Sickle cell disease (SCD) is the most common monogenic hematologic disorder and is essentially congenital hemolytic anemia caused by an inherited point mutation in the β-globin on chromosome 11. Although the genetic basis of SCD was revealed as early as 1957, treatment options for SCD have been very limited to date. Hematopoietic stem cell transplantation (HSCT) was thought to hold promise as a cure for SCD, but the available donors were still only 15% useful. Gene therapy has advanced rapidly into the 21st century with the promise of a cure for SCD, and gene editing strategies based on the cluster-based regularly interspaced short palindromic repeat sequence (CRISPR)/Cas9 system have revolutionized the field of gene therapy by precisely targeting genes. In this paper, we review the pathogenesis and therapeutic approaches of SCD, briefly summarize the delivery strategies of CRISPR/Cas9, and finally discuss in depth the current status, application barriers, and solution directions of CRISPR/Cas9 in SCD. Through the review in this paper, we hope to provide some references for gene therapy in SCD.

Transcriptional enhancers can be in physical proximity of their target genes via chromatin looping. The enhancer at the β-globin locus (locus control region [LCR]) contacts the fetal-type (HBG) and adult-type (HBB) β-globin genes during corresponding developmental stages. We have demonstrated previously that forcing proximity between the LCR and HBG genes in cultured adult-stage erythroid cells can activate HBG transcription. Activation of HBG expression in erythroid cells is of benefit to patients with sickle cell disease. Here, using the β-globin locus as a model, we provide proof of concept at the organismal level that forced enhancer rewiring might present a strategy to alter gene expression for therapeutic purposes. Hematopoietic stem and progenitor cells (HSPCs) from mice bearing human β-globin genes were transduced with lentiviral vectors expressing a synthetic transcription factor (ZF-Ldb1) that fosters LCR-HBG contacts. When engrafted into host animals, HSPCs gave rise to adult-type erythroid cells with elevated HBG expression. Vectors containing ZF-Ldb1 were optimized for activity in cultured human and rhesus macaque erythroid cells. Upon transplantation into rhesus macaques, erythroid cells from HSPCs expressing ZF-Ldb1 displayed elevated HBG production. These findings in two animal models suggest that forced redirection of gene-regulatory elements may be used to alter gene expression to treat disease.

Although risk factors such as cholelithiasis and vaso-occlusive crises exist in sickle cell disease, acute pancreatitis and its recurrence are considered rare complications manifesting as acute abdomen.
UNASSIGNED: A 33-year-old female with sickle cell disease and established cholelithiasis presented to the center with acute abdomen. After examination, investigation, and contrast enhanced computed tomography, acute pancreatitis was diagnosed. Conservative management was done and cholecystectomy was planned but delayed due to low hemoglobin. In the interval she presented again with similar features and diagnosed with of recurrence. After conservative management and after optimization of patient\'s hemodynamic status, laparoscopic cholecystectomy was finally performed. Postoperative period and follow-up visit after 2 months were uneventful.
UNASSIGNED: As the features of pancreatitis and vaso-occlusive crisis are similar, the former should be considered as a differential diagnosis of acute abdomen in sickle cell patients. Laparoscopic cholecystectomy is the treatment of choice for symptomatic cholelithiasis in these patients. However, some issues related to management such as preoperative transfusion and prophylactic cholecystectomy are still debated. This uncertainty caused delay in surgery which may have contributed to the recurrence of pancreatitis in our patient. As the risk of recurrence is possible after the first attack, standard guidelines are required for the definite management of the cause.
UNASSIGNED: This case report adds to the limited literature on recurrent acute pancreatitis in sickle cell patients and points out the need for studies on developing management guidelines in such patients and need for prophylactic treatment.

Thrombosis triggered by platelet activation plays a vital role in the pathogenesis of cardiovascular and cerebrovascular diseases.
This study aims to find platelet combined biomarkers for cardiovascular diseases and investigate the possibility of Concanavalin A (ConA) acting on platelets as a new pharmacological target.
High-throughput Technology and bioinformatics analysis were combined and groups of microarray chip gene expression profiles for acute myocardial infarction (AMI) and sickle cell disease (SCD) were obtained using GEO database screening. R language limma package was used to obtain differentially expressed genes (DEGs). GO, KEGG, and other databases were utilized to perform the enrichment analysis of DEGs\' functions, pathways, etc. PPI network was constructed using STRING database and Cytoscape software, and MCC algorithm was used to obtain the 200 core genes of the two groups of DEGs. Core targets were confirmed by constructing an intersection area screening. A type of molecular probe, ConA, was molecularly docked with the above core targets on the Zdock, HEX, and 3D-DOCK servers.
We found six core markers, CD34, SOCS2, ABL1, MTOR, VEGFA, and SMURF1, which were simultaneously related to both diseases, and the docking effect showed that VEGFA is the best-performing.
VEGFA is most likely to reduce its expression by binding to ConA, which could affect the downstream regulation of the PI3K/Akt signaling pathway during platelet activation. Some other core targets also have the opportunity to interact with ConA to affect platelet-activated thrombosis and trigger changes in cardiovascular events.

Hydroxyurea (HU) is a widely used pharmacological therapy for sickle cell disease (SCD). However, replication stress caused by HU has been shown to inhibit premeiotic S-phase DNA, leading to reproductive toxicity in germ cells. In this study, we administered the therapeutic doses of HU (i.e., 25 and 50 mg/kg) to male mice to explore whether replication stress by HU affects pachytene spermatocytes and causes the abnormalities of homologous chromosomes pairing and recombination during prophase I of meiosis. In comparison with the control group, the proportions of spermatocyte gaps were significantly different in the experimental groups injected with 25 mg/kg (p < 0.05) and 50 mg/kg of HU (p < 0.05). Moreover, the proportions of unrepaired double-stranded breaks (DSBs) observed by γH2AX staining also corresponded to a higher HU dose with a greater number of breaks. Additionally, a reduction in the counts of recombination foci on the autosomal SCs was observed in the pachytene spermatocytes. Our results reveal that HU has some effects on synaptonemal complex (SC) formation and DSB repair which suggest possible problems in fertility. Therefore, this study provides new evidence of the mechanisms underlying HU reproductive toxicity.

Transfusion of red blood cells (RBCs) from ABO-matched but genetically unrelated donors is commonly used for treating anemia and acute blood loss. Increasing demand and insufficient supply for donor RBCs, especially those of universal blood types or free of known and unknown pathogens, has called for ex vivo generation of functional RBCs by large-scale cell culture. However, generating physiological numbers of transfusable cultured RBCs (cRBCs) ex vivo remains challenging, due to our inability to either extensively expand primary RBC precursors (erythroblasts) or achieve efficient enucleation once erythroblasts have been expanded and induced to differentiation and maturation. Here, we report that ectopic expression of the human BMI1 gene confers extensive expansion of human erythroblasts, which can be derived readily from adult peripheral blood mononuclear cells of either healthy donors or sickle cell patients. These extensively expanded erythroblasts (E3s) are able to proliferate exponentially (>1 trillion-fold in 2 months) in a defined culture medium. Expanded E3 cells are karyotypically normal and capable of terminal maturation with approximately 50% enucleation. Additionally, E3-derived cRBCs can circulate in a mouse model following transfusion similar to primary human RBCs. Therefore, we provide a facile approach of generating physiological numbers of human functional erythroblasts ex vivo.