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CRISPER Gene Therapy Recent Trends and Clinical Applications
Published in Yashwant Pathak, Gene Delivery, 2022
Prachi Pandey, Jayvadan Patel, Samarth Kumar
The first clinical trials in the US using CRISPR to catalyze gene disruption for therapeutic benefit were for patients with sickle-cell anemia (SCD) and later β-thalassemia, by Vertex Pharmaceuticals and CRISPR Therapeutics. This therapy, named CTX001, increases fetal hemoglobin (HbF) levels, which can occupy one or two of four hemoglobin binding pockets on erythrocytes, and thereby provides clinical benefit for major β-hemoglobin diseases such as SCD and β-thalassemia. The trial involved collecting autologous hematopoietic stem and progenitor cells from peripheral blood and using CRISPR/Cas9 to disrupt the intronic erythroid-specific enhancer for the BCL11A gene (NCT03745287) as disruption of this gene increases HbF expression. Genetically modified hematopoietic stem cells with BCL11A disruption are delivered by IV infusion after myeloablative conditioning with busulfan to destroy unedited hematopoietic stem cells in the bone marrow. Preliminary findings from two patients receiving this treatment seem promising. One SCD patient was reported to have 46.6% HbF and 94.7% erythrocytes expressing HbF after 4 months of CTX001 transfusions and one β-thalassemia patient is expressing 10.1 g/dL HbF out of 11.9 g/dL total hemoglobin, and 99.8% erythrocytes expressing HbF after 9 months of the therapy. Results from the clinical trial that has opened for this therapy (NCT04208529) to assess the long-term risks and benefits of CTX001 will dictate whether this approach can provide a novel therapeutic opportunity for a disease that otherwise has limited treatment options.
Cytogenetics
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
The t(2;14)(p16;q32) juxtaposing the BCL11A with IGH is very rare but recurrent translocation, and is associated with balky adenopathy, unmutated IGVH, and atypical morphology and immunophenotype.
Primary mediastinal (thymic) large B-cell lymphoma
Published in Franco Cavalli, Harald Stein, Emanuele Zucca, Extranodal Lymphomas, 2008
Kerry J Savage, Philippe Gaulard
Comparative genomic hybridization (CGH) studies, have shown that PMBCL is characterized by distinctive chromosomal aberrations, including recurrent chromosomal gains in 9p23-24 in approximately 70% of cases, in addition to gains in chromosome 2p15 (~50%), Xp11.4-21 (33%), Xq24-26 (33%), 7q22 (32%), 9q34 (32%), and 12q31 (30%).28–31 This genomic profile is unique among DLBCL. The biological significance of these alterations is not fully understood. However, candidate genes include REL and BCL11A, at chromosome 2p, which are amplified in a proportion of PMBCL, leading to frequent nuclear accumulation of their respective proteins.22,32,33 At chromosome 9p, amplification of JAK2 – a gene which is involved in cytokine-dependent signal transduction – has been demonstrated in a proportion of cases.23,28,34 Despite amplification at the genetic level, JAK2 does not appear to be over-expressed at the RNA level in many cases, and increased JAK2 activity has rather been associated with mutations in the suppressor of cytokine signaling (SOCS1) gene.34 The PMBCL cell lines MEDB-1 and Karpas 1106 have biallelic mutations and deletions in SOCS1, respectively, both resulting in constitutive activation of the JAK–STAT pathway. Mutations or deletions in SOCS1 have also been recently found in 45% of PMBCL primary tumors (see Table 18.1) and more recently cHL cell lines as well as in laser microdissected Reed–Sternberg cells of 40% of cHL primary tumors, supporting that this oncogenic pathway is prominent in both tumors.34–36 The amplicon on chromosome 9p also includes PDL1 and PDL2, which encode members of the B7 family and are ligands for the PD-1 receptor on T-cells; however, the pathogenic significance in PMBCL is unknown.
Targeting fetal hemoglobin expression to treat β hemoglobinopathies
Published in Expert Opinion on Therapeutic Targets, 2022
Insights into the controls of gene expression in the HBB gene cluster has presented new targets for partially reversing the hemoglobin switch [11]. These controls are complex, have been the subject of excellent reviews, and are briefly discussed to provide context for identifying targets for HbF-induction [9–13]. BCL11A has a central role in HBG regulation by forming repressor complexes with multiple proteins and chromatin modifiers (Figure 2). Among other elements involved are lysine-specific demethylase-1 (LSD and DNA methyltransferase-1, DNMT1) and the nucleosome remodeling and histone deacetylase (NuRD) complexes that include histone deacetylases (HDAC1, HDAC2) and chromodomain helicase DNA binding protein 4 (CHD4). All have been targeted for their potential to induce HBG expression.
Sickle cell disease in the era of precision medicine: looking to the future
Published in Expert Review of Precision Medicine and Drug Development, 2019
Martin H Steinberg, Sara Kumar, George J. Murphy, Kim Vanuytsel
BCL11A, chromosome 2 QTL, encodes a zinc-finger protein that represses the γ-globin genes by binding their promoters, as discussed above. The genetic association of BCL11A with HbF levels was proven in studies of multiple cohorts of normal individuals and patients with sickle cell anemia and β thalassemia [25,31]. BCL11A favorably modified the features of both diseases because of its effects on HbF concentration [32,33]. Sentinel SNPs marking the effects of BCL11A on HbF were located in the second intron of this gene in an erythroid-specific gene enhancer. The high HbF-associated SNP is common and also has a large effect size [34,35]. High-resolution studies of BCL11A binding sites in the HBB gene cluster suggested that promoter repression was the major mechanism of action of this protein that controls most of the hemoglobin switching.
BCL11A Down-Regulation Induces γ-Globin in Human β-Thalassemia Major Erythroid Cells
Published in Hemoglobin, 2018
Jing Li, Yongrong Lai, Lingling Shi
BCL11A isoforms have been shown to be expressed in human erythroid cells [10], yet whether there are differential roles for these various isoforms (particularly the full-length forms that are robustly expressed in adult erythroid cells and include both the XL and L isoforms) remains unknown. In addition, it is also not clear if there are unknown roles of BCL11A in vivo.