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Pyruvate kinase deficiency: advanced therapies for the treatment of erythroid metabolic diseases

Pyruvate kinase deficiency ( PKD ) is a monogenic metabolic disease caused by mutations in the PKLR gene that impairs energetic balance in erythrocytes causing hemolytic anemia in a very variable range and can be even fatal during neonatal period.
PKD recessive inheritance trait and its curative treatment by allogeneic bone marrow transplantation, provide an ideal scenario for developing gene therapy approaches.

Researchers have designed a preclinical protocol based on hematopoietic stem cell ( HSC ) genetic modification and transplantation into PKD mice. The therapeutic lentiviral vector developed included the hPGK eukaryotic promoter driving the expression of the PKLR cDNA, achieving clinically relevant levels of the protein and an efficient and safe correction of PKD phenotype.

Although successful addition gene therapy trials are currently being applied in the clinics, ideal gene therapy will be based on gene correction strategies based on homologous recombination ( HR ).

Induced pluripotent stem cells ( hiPSC ) were first generated from peripheral blood mononuclear cells ( PB-MNC ) of PKD patients ( PKDiPSCs ) using Sendai vectors. Thereafter, the genetic defect of these cells was corrected by TALEN ( transcription activator-like effector nuclease )-mediated HR in the PKLR locus.

As deduced from the normal erythroid maturation profile of corrected PKDiPSCs, the compromised erythroid differentiation of these cells was restored. ( Xagena )

Garcıa-Gomez M et al, Human Gene Therapy, 2013