Abstract
The erythroid related disorders (ERDs) represent a large group of hematological diseases, which in most cases are attributed either to the deficiency or malfunction of biosynthetic enzymes or oxygen transport proteins. Current treatments for these disorders include histo-compatible erythrocyte transfusions or allogeneic hematopoietic stem cell (HSC) transplantation. Gene therapy delivered via suitable viral vectors or genetically modified HSCs have been under way. Protein Transduction Domain (PTD) technology has allowed the production and intracellular delivery of recombinant therapeutic proteins, bearing Cell Penetrating Peptides (CPPs), into a variety of mammalian cells. Remarkable progress in the field of protein transduction leads to the development of novel protein therapeutics (CPP-mediated PTs) for the treatment of monogenetic and/or metabolic disorders. The “concept” developed in this paper is the intracellular protein delivery made possible via the PTD technology as a novel therapeutic intervention for treatment of ERDs. This can be achieved via four stages including: (i) the production of genetically engineered human CPP-mediated PT of interest, since the corresponding native protein either is missing or is mutated in the erythroid progenitor cell (ErPCs) or mature erythrocytes of patients; (ii) isolation of target cells from the peripheral blood of the selected patients; (iii) ex vivo transduction of cells with the CPP-mediated PT of interest; and (iv) re-administration of the successfully transduced cells back into the same patients.
Highlights
Erythropoiesis is a complex developmental process occurring in bone marrow (BM) during adult life
Erythropoiesis involves: (i) activation of the erythropoietin (EPO) receptor mediated signaling by EPO; EPO is promoted by hypoxia via the hypoxia-inducible transcription factors; (ii) activation of heme biosynthesis; (iii) expression of globin genes; and (iv) completion of terminal morphological maturation [1,2]
The poor availability of transplants from HLA - matched donors, the severity of graft versus host disease (GVHD) that can be developed in cases of allogeneic hematopoietic stem cell (HSC) transplantation (HSCT) and the complexities associated with gene therapy demand alternative therapeutic interventions for erythroid related disorders (ERDs)
Summary
Erythropoiesis is a complex developmental process occurring in bone marrow (BM) during adult life. There are other disorders that affect mainly hematopoietic progenitor cells, like the myeloproliferative polycythemia vera, the acute erythroid leukemia and the myelodysplastic syndromes The latter are characterized by overwhelming or ineffective erythropoiesis [13], accompanied by known and unknown genetic abnormalities. The poor availability of transplants from HLA - matched donors, the severity of graft versus host disease (GVHD) that can be developed in cases of allogeneic HSC transplantation (HSCT) and the complexities associated with gene therapy (like insertional mutagenesis - tumorigenesis) demand alternative therapeutic interventions for ERDs. Enzyme or protein replacement therapy (ERT/PRT) via the Protein Transduction Domain (PTD). In the framework of this “concept paper”, we wish: (i) to discuss the pathophysiology and current treatment - management of some ERDs (sideroblastic anemias, porphyrias and hemoglobinopathies); and (ii) to present how CPP-mediated PTs (biodrugs) can be used as an alternative ERT/PRT approach for treating ERDs
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