Use of MicroRNA in treating kit-dependent tumors, and inhibitors of MicroRNA

RNAs, which plays an important role in the negative regulation of gene expression by base-pairing to complementary sites on the target mRNAs.miRs are involved in basic biological processes.

Summary of Invention The invention relates to the use of micro RNAs in therapy. Micro RNAs (miRs) are a recently discovered class of small (~22nt) RNAs, which plays an important role in the negative regulation of gene expression by base-pairing to complementary sites on the target mRNAs . In excess of 300 miRs have so far been identified in eukaryotes. Growing evidence indicates that miRs are involved in basic biological processes, e.g.: cell proliferation and apoptosis (11,12); neural development and haematopoiesis (13); fat metabolism; stress response; and cancer (14-16), via the targeting of key functional mRNAs. Inventors have found that treatment of CD34+ cells with two naturally occurring micro RNAs, miR221 and miR222, causes impaired proliferation and accelerated differentiation of erythroid cells, coupled with down- modulation of kit protein, while levels of kit mRNA are unaffected, and that miR221 and miR222 gene transfer blocks proliferation of the TF1 erythroleukemic cell line. Treatment with anti-miR221 and miR222 oligonucleotides causes the opposite effect. Thus, surprisingly, they have now found that miR 221 and miR 222 can each inhibit or block translation of kit mRNA. The invention provides antisense RNA specific for all or part of the 3' untranslated region of kit protein mRNA. More particularly, the present invention provides the use of antisense RNA specific for all or part of the 3' untranslated region of kit protein mRNA in therapy. The nature of the therapy is any that is affected by expression of kit protein. In particular, antisense RNAs of the present invention may be used in the treatment of GIST (gastro-intestinal stromal tumor), kit-dependent acute leukaemias and other kit-dependent tumors. The invention further provides miR 221 and miR 222 inhibitors (antibodies and sense RNA sequences), and their use in therapy. MiR 221 and miR 222 are naturally occurring, and high levels of these micro RNAs inhibit erythropoiesis, and this effect can be undesirable, such as with cancer patients undergoing chemotherapy, which can repress erythropoiesis. Accordingly, the present invention provides the use of an miR 221 and miR 222 inhibitor in therapy. Conditions treatable by miR 221 and miR 222 inhibitors include suppressed haematopoiesis in cancer patients and ?- thalassemia and other ?-haemoglobin diseases. In _-thalassemia and other _ -haemoglobin diseases, e.g, sickle cell anemia, miR 221 and miR 222 inhibitors may be used to enhance the level of _-globin synthesis, thus leading to a therapeutic effect. Such inhibitors may also be used for the potentiation of ex vivo expansion of haematopoietic stem/progenitor cells and for the enhancement of the proliferative and anti-apoptotic effects of kit in non-haematopoietic cells, whether such cells be of a normal or abnormal phenotype. Solution to which problem (s) The invention provide a solution for the therapy of kit-dependent tumors and for the expansion of erythropoiesis. Key applications • antisense RNAs therapy of gastro-intestinal stromal tumor , kit- dependent acute leukaemias and other kit-dependent tumors. • Use of miR 221 and miR 222 inhibitors to enhance the level of _-globin synthesis, thus leading to a therapeutic effect in _-thalassemia and other _ -haemoglobin diseases, e.g, sickle cell anemia. • Use of miR 221 and miR 222 inhibitors the potentiation of ex vivo expansion of haematopoietic stem/progenitor cells and for the enhancement of the proliferative and anti-apoptotic effects of kit in non- haematopoietic cells. Stage of Development: The technology is in the pre-clinical stage with in vivo animal studies ongoing.

Early Stage

Priority filing in UK in Apr. 15, 2005

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