Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse β<sup>IVS2-654</sup>-Thalassemic Erythroid Progenitor Cells

d'Arqom, Annette; Nualkaew, Tiwaporn; Jearawiriyapaisarn, Natee; Kole, Ryszard; Svasti, Saovaros

doi:10.1089/hum.2020.145

Cited by 6 publications

(4 citation statements)

References 21 publications

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“…Heterozygous β IVS2-654thalassaemic mice recapitulate the characteristics of β-thalassaemia patients including anaemia, abnormal red blood cell indices, increased ROS levels in red blood cells, increased red blood cell-derived vesicles, splenomegaly, iron overload and osteoporosis [20][21][22] . The mouse model was also used as model for the study of a novel therapy for β-thalassaemia through restoration of β-globin pre-mRNA splicing using splice switching oligonucleotide 23,24 .…”

Section: Discussionmentioning

confidence: 99%

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Chaichompoo

Nithipongvanitch

Kheansaard

et al. 2022

Sci Rep

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Abstractβ-Thalassaemia results from defects in β-globin chain production, leading to ineffective erythropoiesis and subsequently to severe anaemia and other complications. Apoptosis and autophagy are the main pathways that regulate the balance between cell survival and cell death in response to diverse cellular stresses. Herein, the death of erythroid lineage cells in the bone marrow from both βIVS2-654-thalassaemic mice and β-thalassaemia/HbE patients was investigated. Phosphatidylserine (PS)-bearing basophilic erythroblasts and polychromatophilic erythroblasts were significantly increased in β-thalassaemia as compared to controls. However, the activation of caspase 8, caspase 9 and caspase 3 was minimal and not different from control in both murine and human thalassaemic erythroblasts. Interestingly, bone marrow erythroblasts from both β-thalassaemic mice and β-thalassaemia/HbE patients had significantly increased autophagy as shown by increased autophagosomes and increased co-localization between LC3 and LAMP-1. Inhibition of autophagy by chloroquine caused significantly increased erythroblast apoptosis. We have demonstrated increased autophagy which led to minimal apoptosis in β-thalassaemic erythroblasts. However, increased PS exposure occurring through other mechanisms in thalassaemic erythroblasts might cause rapid phagocytic removal by macrophages and consequently ineffective erythropoiesis in β-thalassaemia.

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Section: Discussionmentioning

confidence: 99%

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Chaichompoo

Nithipongvanitch

Kheansaard

et al. 2022

Sci Rep

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“…Several gene therapies have been approved as treatments for rare genetic diseases such as Eteplirsen for DMD [ 19 ], Zolgensma and nusinersen for SMA [ 36 , 37 ], Luxturna for inherited retinal dystrophy [ 17 ], LentiGlobin or Zynteglo for thalassemia [ 21 ], CAR-T cell for leukemia and lymphoma [ 16 ], and many more in progress [ 38–40 ]. Since their launch, debates on their clinical values and price remain ongoing and some studies have endeavored to show the benefit of these approved gene therapies.…”

Section: Discussionmentioning

confidence: 99%

Medical Student Acceptance on Gene Therapy to Increase children's well-being With Genetic Diseases: a Study in Indonesia

et al. 2022

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Aim: Gene therapy is expected to improve patients' quality of life. Medical students need to be aware about this technology as its application is becoming wider. Materials & methods: A web-based survey was conducted to measure the acceptance of Indonesian medical students regarding gene therapy. Results: Data from 621 valid responses showed that Indonesian medical students have little knowledge of this technology, with 34.4% of them ever heard of gene therapy. However, most of them support the approved gene therapy for health-related matters, but not on the non-health related matters. Their acceptance was determined by the sex, domicile and studentship status. Conclusion: Increasing medical students' knowledge of gene therapy is important to minimize the future conflict of gene therapy application.

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“…This situation was probably due to an inefficient processing of U7 snRNA in mouse thus producing truncated engineered U7 snRNA. The different processing of U7 snRNA in humans and mice has therefore restricted the depth analysis of the engineered U7 snRNA in the mouse model ( 31 ).…”

Section: Rna Manipulation Strategiesmentioning

confidence: 99%

Genetic Manipulation Strategies for β-Thalassemia: A Review

Zakaria

Bahar²,

Abdullah³

et al. 2022

Front. Pediatr.

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Thalassemias are monogenic hematologic diseases that are classified as α- or β-thalassemia according to its quantitative abnormalities of adult α- or β-globin chains. β-thalassemia has widely spread throughout the world especially in Mediterranean countries, the Middle East, Central Asia, India, Southern China, and the Far East as well as countries along the north coast of Africa and in South America. The one and the only cure for β-thalassemia is allogenic hematopoietic stem cell transplantations (HSCT). Nevertheless, the difficulty to find matched donors has hindered the availability of this therapeutic option. Therefore, this present review explored the alternatives for β-thalassemia treatment such as RNA manipulation therapy, splice-switching, genome editing and generation of corrected induced pluripotent stem cells (iPSCs). Manipulation of β-globin RNA is mediated by antisense oligonucleotides (ASOs) or splice-switching oligonucleotides (SSOs), which redirect pre-mRNA splicing to significantly restore correct β-globin pre-mRNA splicing and gene product in cultured erythropoietic cells. Zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) are designer proteins that can alter the genome precisely by creating specific DNA double-strand breaks. The treatment of β-thalassemia patient-derived iPSCs with TALENs have been found to correct the β-globin gene mutations, implying that TALENs could be used as a therapy option for β-thalassemia. Additionally, CRISPR technologies using Cas9 have been used to fix mutations in the β-globin gene in cultured cells as well as induction of hereditary persistence of fetal hemoglobin (HPFH), and α-globin gene deletions have proposed a possible therapeutic option for β-thalassemia. Overall, the accumulated research evidence demonstrated the potential of ASOs-mediated aberrant splicing correction of β-thalassemia mutations and the advancements of genome therapy approaches using ZFNs, TALENs, and CRISPR/Cas9 that provided insights in finding the permanent cure of β-thalassemia.

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Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse β^IVS2-654-Thalassemic Erythroid Progenitor Cells

Cited by 6 publications

References 21 publications

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Medical Student Acceptance on Gene Therapy to Increase children's well-being With Genetic Diseases: a Study in Indonesia

Genetic Manipulation Strategies for β-Thalassemia: A Review

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Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse βIVS2-654-Thalassemic Erythroid Progenitor Cells

Cited by 6 publications

References 21 publications

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Increased autophagy leads to decreased apoptosis during β-thalassaemic mouse and patient erythropoiesis

Medical Student Acceptance on Gene Therapy to Increase children's well-being With Genetic Diseases: a Study in Indonesia

Genetic Manipulation Strategies for β-Thalassemia: A Review

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Engineered U7 Small Nuclear RNA Restores Correct β-Globin Pre-mRNA Splicing in Mouse β^IVS2-654-Thalassemic Erythroid Progenitor Cells