Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia

Jaako, Pekka; Debnath, Shubhranshu; Olsson, Karin; Modlich, Ute; Rothe, Michael; Schambach, Axel; Flygare, Johan; Karlsson, Stefán

doi:10.3324/haematol.2014.111195

Cited by 27 publications

(21 citation statements)

References 29 publications

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“…15 Importantly, the hematopoietic phenotype in these mice is specific to Rps19 downregulation as it can be cured by enforced expression of RPS19. 15,26 We intercrossed the shRNA-B mice with the Mdm2 C305F knock-in mice that have a point mutation in the zinc finger domain of Mdm2, which prevents its binding to 5S RNP (Figure 1b). 23,24 As a consequence, these mice present with an attenuated p53 response upon ribosome biogenesis stress, but retain a normal response to DNA damage.…”

Section: Resultsmentioning

confidence: 99%

Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

et al. 2015

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Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia caused by haploinsufficiency of genes encoding ribosomal proteins (RPs). Perturbed ribosome biogenesis in DBA has been shown to induce a p53-mediated ribosomal stress response. However, the mechanisms of p53 activation and its relevance for the erythroid defect remain elusive. Previous studies have indicated that activation of p53 is caused by the inhibition of mouse double minute 2 (Mdm2), the main negative regulator of p53, by the 5S ribonucleoprotein particle (RNP). Meanwhile, it is not clear whether this mechanism solely mediates the p53-dependent component found in DBA. To approach this question, we crossed our mouse model for RPS19-deficient DBA with Mdm2C305F knock-in mice that have a disrupted 5S RNP–Mdm2 interaction. Upon induction of the Rps19 deficiency, Mdm2C305F reversed the p53 response and improved expansion of hematopoietic progenitors in vitro, and ameliorated the anemia in vivo. Unexpectedly, disruption of the 5S RNP–Mdm2 interaction also led to selective defect in erythropoiesis. Our findings highlight the sensitivity of erythroid progenitor cells to aberrations in p53 homeostasis mediated by the 5S RNP–Mdm2 interaction. Finally, we provide evidence indicating that physiological activation of the 5S RNP-Mdm2-p53 pathway may contribute to functional decline of the hematopoietic system in a cell-autonomous manner over time.

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Section: Resultsmentioning

confidence: 99%

Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

et al. 2015

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“…After they were treated with viral vectors carrying the RPS19 gene, these cells recovered their protein synthesis and levels of p53 also dropped [ 31 ]. Another study reported the efficacy of gene therapy by exhibiting successful treatment of RPS19-deficient DBA mouse models following gene transfer [ 32 ]. Stimulation of RPS19 gene expression in RPS19-deficient cells by the transfer of lentiviral vector with cDNA of elongation factor 1 α short (EFS) promoter has also been documented [ 33 ].…”

Section: Reviewmentioning

confidence: 99%

A Review of Diamond-Blackfan Anemia: Current Evidence on Involved Genes and Treatment Modalities

Tyagi¹,

Gupta²,

Dutta³

et al. 2020

Cureus

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Diamond-Blackfan anemia (DBA) is a congenital cause of bone marrow failure predominantly involving the erythroid cell line, with occasional impact on other cell lines. In the vast majority of cases, it is diagnosed by one year of age. We looked at the existing literature on the disease presentation along with established as well as upcoming treatment options. Numerous genes have been identified and extensively studied in the context of their part in the pathogenesis of DBA. Treatment revolves around the use of steroids and regular blood transfusions, with hematopoietic stem cell transplantation reserved for steroid-resistant cases. Newer modalities such as gene therapy, l-leucine, sotatercept, trifluoperazine, SMER28, and danazol are also concisely discussed. The purpose of this article is to review the previous literature on DBA and weigh the role of newer therapeutic agents.

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“…Gene therapy studies conducted in a conditional RPS19 knock‐down mouse model with SIN‐LVs showed that the ectopic expression of RPS19 prevented the lethal BMF characteristic of these animals . Because these studies used LVs harboring the strong SFFV promoter, subsequent studies were carried out with a more clinically relevant EFSα‐RPS19 LV .…”

Section: Gene Therapy In Inherited Bone Marrow Failure Syndromesmentioning

confidence: 99%

Advances in the gene therapy of monogenic blood cell diseases

et al. 2019

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Hematopoietic gene therapy has markedly progressed during the last 15 years both in terms of safety and efficacy. While a number of serious adverse events (SAE) were initially generated as a consequence of genotoxic insertions of gamma-retroviral vectors in the cell genome, no SAEs and excellent outcomes have been reported in patients infused with autologous hematopoietic stem cells (HSCs) transduced with self-inactivated lentiviral and gammaretroviral vectors. Advances in the field of HSC gene therapy have extended the number of monogenic diseases that can be treated with these approaches. Nowadays, evidence of clinical efficacy has been shown not only in primary immunodeficiencies, but also in other hematopoietic diseases, including beta-thalassemia and sickle cell anemia. In addition to the rapid progression of non-targeted gene therapies in the clinic, new approaches based on gene editing have been developed thanks to the discovery of designed nucleases and improved non-integrative vectors, which have markedly increased the efficacy and specificity of gene targeting to levels compatible with its clinical application. Based on advances achieved in the field of gene therapy, it can be envisaged that these therapies will soon be part of the therapeutic approaches used to treat life-threatening diseases of the hematopoietic system.

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Gene therapy cures the anemia and lethal bone marrow failure in a mouse model of RPS19-deficient Diamond-Blackfan anemia

Cited by 27 publications

References 29 publications

Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

Disruption of the 5S RNP–Mdm2 interaction significantly improves the erythroid defect in a mouse model for Diamond-Blackfan anemia

A Review of Diamond-Blackfan Anemia: Current Evidence on Involved Genes and Treatment Modalities

Advances in the gene therapy of monogenic blood cell diseases

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