Safe and efficient gene therapy for pyruvate kinase deficiency

Maria Garcia-Gomez, Andrea Calabria, Maria Garcia-Bravo, Fabrizio Benedicenti, Penelope Kosinski, Sergio López-Manzaneda, Collin Hill, María Del Mar Mau-Pereira, Miguel A. Martín, Israel Orman, Joan Lluis Vives-Corrons, Charles Kung, Axel Schambach, Shengfang Jin, Juan A. Bueren, Eugenio Montini, Susana Navarro, Jose C. Segovia

Research output: Contribution to journalArticlepeer-review


Pyruvate kinase deficiency (PKD) is a monogenic metabolic disease caused by mutations in the PKLR gene that leads to hemolytic anemia of variable symptomatology and that can be fatal during the neonatal period. PKD recessive inheritance trait and its curative treatment by allogeneic bone marrow transplantation provide an ideal scenario for developing gene therapy approaches. Here, we provide a preclinical gene therapy for PKD based on a lentiviral vector harboring the hPGK eukaryotic promoter that drives the expression of the PKLR cDNA. This therapeutic vector was used to transduce mouse PKD hematopoietic stem cells (HSCs) that were subsequently transplanted into myeloablated PKD mice. Ectopic RPK expression normalized the erythroid compartment correcting the hematological phenotype and reverting organ pathology. Metabolomic studies demonstrated functional correction of the glycolytic pathway in RBCs derived from genetically corrected PKD HSCs, with no metabolic disturbances in leukocytes. The analysis of the lentiviral insertion sites in the genome of transplanted hematopoietic cells demonstrated no evidence of genotoxicity in any of the transplanted animals. Overall, our results underscore the therapeutic potential of the hPGK-coRPK lentiviral vector and provide high expectations toward the gene therapy of PKD and other erythroid metabolic genetic disorders.

Original languageEnglish
Pages (from-to)1187-1198
Number of pages12
JournalMolecular Therapy
Issue number7
Publication statusPublished - Aug 1 2016

ASJC Scopus subject areas

  • Medicine(all)
  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery


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