Clinically relevant gene editing in hematopoietic stem cells for the treatment of pyruvate kinase deficiency

Fañanas-Baquero, Sara; Quintana-Bustamante, Óscar; Dever, Daniel P.; Alberquilla, Omaira; Sanchez-Dominguez, Rebeca; Camarena, Joab; Ojeda-Pérez, Isabel; Dessy-Rodriguez, Mercedes; Turk, Rolf; Schubert, Mollie S.; Lattanzi, Annalisa; Xu, Liwen; López-Lorenzo, José Luis; Bianchi, Paola; Bueren, Juan A.; Behlke, Mark A.; Porteus, Matthew H.; Segovia, José C.

doi:10.1016/j.omtm.2021.05.001

Cited by 13 publications

(21 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, the mutated HBB gene has been gene edited to recover a fully functional β-globin protein through the correction of sickle cell mutation ( Dever et al, 2016 ; DeWitt et al, 2016 ; Hoban et al, 2016 ; Lattanzi et al, 2021 ; Wilkinson et al, 2021 ). Additionally, another inherited erythroid disease, PKD, has been proposed to be corrected through CRISPR/Cas gene editing ( Fañanas-Baquero et al, 2021 ).…”

Section: Gene Editing Technologymentioning

confidence: 99%

“…Currently, the combination of electroporation for nuclease entry and viral vectors for donor template delivery is the chosen option for some gene editing approaches ( Genovese et al, 2014 ; Dever et al, 2016 ; De Ravin et al, 2017 ; Fañanas-Baquero et al, 2021 ).…”

Section: Delivery Of Gene Editing Toolsmentioning

confidence: 99%

“…Up to 70% of HSPCs can be transduced without altering their engraftment ability. Electroporation of nucleases in combination with rAAV6 to introduce large donor template, has been selected as a very efficient delivery method to gene edit HSPCs for gene therapy of inherited anemias, such as hemoglobinopathies ( Dever et al, 2016 ; Hoban et al, 2016 ; Lattanzi et al, 2021 ; Wilkinson et al, 2021 ) and PKD ( Fañanas-Baquero et al, 2021 ), and other hematopoietic diseases, such as X-linked chronic granulomatous disease (X-CGD) ( De Ravin et al, 2017 ), Wiskott-Aldrich síndrome (WAS) ( Rai et al, 2020 ).…”

Section: Delivery Of Gene Editing Toolsmentioning

confidence: 99%

“…To favor this HDR, the exogenous DNA that is intended to be introduced into the genome has to be flanked by homologous arm sequences complementary to the region close to the DSB. HDR has been used to introduce large donor templates, with therapeutic cDNA to compensate the function of the mutated gene, as potential treatment for hemoglobinopathies ( Dever et al, 2016 ) as well as other RBC inherited diseases such as PKD ( Fañanas-Baquero et al, 2021 ).…”

Section: Gene Editing Strategiesmentioning

confidence: 99%

“…The introduction of a large therapeutic donor, as mentioned previously, would offer a global solution for all patients, regardless of the nature of the mutation that they carry. Clinically applicable results (up to 70% edited HSPCs) have been obtained using CRISPR/Cas9 system combined with rAAV6 vector in HSPC to correct inherited hematopoietic diseases such as hemoglobinopathies ( Dever et al, 2016 ; Hoban et al, 2016 ; Lattanzi et al, 2021 ; Wilkinson et al, 2021 ), and other hematopoietic diseases such as ase X-CGD ( De Ravin et al, 2017 ), WAS ( Rai et al, 2020 ) and PKD ( Fañanas-Baquero et al, 2021 ). In a seminal paper, Dever et al (2016) described specific correction of 50% of the sickling mutation in SCD patient-derived HSPCs.…”

Section: Gene Editing Strategiesmentioning

confidence: 99%

See 4 more Smart Citations

Gene Editing for Inherited Red Blood Cell Diseases

et al. 2022

Self Cite

View full text Add to dashboard Cite

Today gene therapy is a real therapeutic option to address inherited hematological diseases that could be beneficial for thousands of patients worldwide. Currently, gene therapy is used to treat different monogenic hematological pathologies, including several red blood cell diseases such as β-thalassemia, sickle cell disease and pyruvate kinase deficiency. This approach is based on addition gene therapy, which consists of the correction of hematopoietic stem cells (HSCs) using lentiviral vectors, which integrate a corrected version of the altered gene. Lentivirally-corrected HSCs generate healthy cells that compensate for the deficiency caused by genetic mutations. Despite its successful results, this approach lacks both control of the integration of the transgene into the genome and endogenous regulation of the therapeutic gene, both of which are important aspects that might be a cause for concern. To overcome these limitations, gene editing is able to correct the altered gene through more precise and safer approaches. Cheap and easy-to-design gene editing tools, such as the CRISPR/Cas9 system, allow the specific correction of the altered gene without affecting the rest of the genome. Inherited erythroid diseases, such as thalassemia, sickle cell disease and Pyruvate Kinase Deficiency, have been the test bed for these gene editing strategies, and promising results are currently being seen. CRISPR/Cas9 system has been successfully used to manipulate globin regulation to re-activate fetal globin chains in adult red blood cells and to compensate for hemoglobin defects. Knock-in at the mutated locus to express the therapeutic gene under the endogenous gene regulatory region has also been accomplished successfully. Thanks to the lessons learned from previous lentiviral gene therapy research and trials, gene editing for red blood cell diseases is rapidly moving from its proof-of-concept to its first exciting results in the clinic. Indeed, patients suffering from β-thalassemia and sickle cell disease have already been successfully treated with gene editing, which will hopefully inspire the use of gene editing to cure erythroid disorders and many other inherited diseases in the near future.

show abstract