Site-specific genome editing for hematopoetic stem cells transplantation-based gene therapy approaches



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Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) remains the sole universal curative approach for a number of hereditary diseases, such as severe combined immunodeficiency (SCID), severe non-SCID primary immunodeficiencies (non-SCID PID), hematologic diseases and part of lysosomal storage disorders. Unfortunately, to date, HSCT remains a high-risk procedure, especially in cases of poor performance status of the patient and lack of HLA-matched related donors. In those cases the correction of the patients autologous HSCs with gene therapy could be a promising alternative. Current paradigm of HSCT-based gene therapy approaches is based on the utilization of viral vectors, which may lead to the severe complications due to insertion mutagenesis. Throughout the last several years, new technologies of site-specific genome editing with endonucleases such as ZFNs, TALENs, and CRISPR/Cas9 were introduced. These enzymes may induce a DNA doublestranded break, homology-directed repair and insertion of functional copy of gene in precisely targeted locus. This review focuses on the advantages and disadvantages of the genome editing tools utilization that carries the great potential of changing the paradigm of gene therapy in the setting of HSCT.

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About the authors

K. V Lepik

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

M. O Popova

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Email: marina.popova.spb@gmail.com
Saint-Petersburg, Russia

A. I Shakirova

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

V. S Sergeev

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

A. Y Potter

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

I. M Barkhatov

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

B. Fehse

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation; University Medical Center (UKE] Hamburg-Eppendorf

Saint-Petersburg, Russia; Hamburg, Germany

B. V Afanasyev

R.M. Gorbacheva Research Institute for Pediatric Oncology, Hematology and Transplantation

Saint-Petersburg, Russia

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