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METHOD FOR TREATING BLOOD DISEASES
WO22129308
The present invention refers to a method for treating neutropenia and/or for the activation of myelopoiesis. For that purpose, affinity reagents, preferably aptamers, have been developed in the present invention which specifically bind the telomerase RNA component (TERC)DNA-binding-site. Aptamers are promising alternatives to antibodies and can be used as high affinity agents for the treatment of diseases. Therefore, several aptamers based on the TERC sequence were designed to investigate whether these small molecules could also increase myelopoiesis. Two aptamers were able to increase the number of neutrophils and macrophages, without affecting the number of erythrocytes in zebrafish models. Aptamers function as the complete TERC molecule; that is, regulating the expression of the main myelopoiesis genes by binding to specific DNA sequences in the regulatory regions of these target genes and recruiting RNA Pol lI to activate transcription. Using preclinical zebrafish models of diseases that occur with neutropenia, such as dyskeratosis congenita (DC, TERC deficiency) and poikiloderma disease with neutropenia (USB1 deficiency), the therapeutic effect of the developed aptamers was demonstrated, where the reversion was observed. of neutropenias. Furthermore, treatment using the corresponding humanized aptamers also increased the expression of myelopoiesis regulatory genes and restored myelopoiesis in induced pluripotent cells (iPSCs) from healthy donor and DC patients with TERC mutations.
The currently available treatment for neutropenia is the administration of granulocyte colony stimulating factor (G-CSF). G-CSF has been approved by the FDA and EMA for the treatment of congenital and acquired neutropenia and for the mobilization of peripheral hematopoietic progenitor cells for stem cell transplantation. Furthermore, G-CSF has been used in patients with DC, being relatively effective in children and young adults. However, G-CSF treatment has some mild side effects (dyspnea, chest pain, nausea, hypoxemia, sweating, anaphylaxis, syncope flush, splenomegaly), but the major disadvantages are its high cost and its ability to promote syndrome. myelodysplastic and myeloid leukaemia in various clinical circumstances. Therefore, there is an unmet medical need to find efficient and safer therapies for the treatment of neutropenia (or diseases derived therefrom) and / or for the activation of myelopoiesis. On the other hand, It is known aptamers have an excellent pharmacokinetic properties, low toxicity, and low production cost of aptamers, we believe the aptamers designed in this study might be considered as potential therapeutic tools for clinical trial