Therapeutic oligonucleotides

Abstract

The present invention relates to an oligonucleotide comprising one of the following sequence: (TTAGGG) SEQ ID No. 1, (TAGGGT) SEQ ID No. 2, (AGGGTT) SEQ ID No. 3, (GGGTTA) SEQ ID No. 4, (GGTTAG) SEQ ID No. 5 or (GTTAGG) SEQ ID No. 6 or a complementary sequence thereof or a fragment or a variant or a mixture thereof for use in the treatment and/or prevention of a disease characterized by alternative lengthening of telomeres or a non-cancer condition associated with telomere dysfunction and relative pharmaceutical compositions and to relative pharmaceutical composition and method.

1 . An oligonucleotide comprising at least one of the following sequences:
 (TTAGGG) SEQ ID No. 1, (TAGGGT) SEQ ID No. 2, (AGGGTT) SEQ ID No. 3, (GGGTTA) SEQ ID No. 4, (GGTTAG) SEQ ID No. 5 or (GTTAGG) SEQ ID No. 6 or a variant or a mixture thereof for use in the treatment and/or prevention of a disease characterized by alternative lengthening of telomeres wherein the variant comprises one of the following sequence: TCAGGG, TTCGGG, GTAGGG, TGAGGG, TTGGGG, TAAGGG, ATAGGG, CTAGGG, TTTGGG or TTAAGGG.   
     
     
         2 . The oligonucleotide or a variant thereof for use according to  claim 1  comprising at least one of the following sequences: (TTAGGG) n , (TAGGGT) n , (AGGGTT) n , (GGGTTA) n , (GGTTAG) n  or (GTTAGG) n  wherein 1<n<1000, preferably 1<n<500, preferably 1<n<200, preferably 1<n<100, preferably 1<n<50, preferably 1<n<20, preferably 1<n<10, preferably 1<n<5. 
     
     
         3 . The oligonucleotide for use according to  claim 1  wherein said oligonucleotide is complementary to the sequence of an RNA, said RNA being a RNA transcript synthesized using a specific dysfunctional telomeric DNA as a template for transcription or a fragment of said RNA transcript, said fragment (DDRNA) being generated by processing by Dicer and/or Drosha. 
     
     
         4 . The oligonucleotide for use according to  claim 1  wherein the disease is cancer or an Epstein-Bar virus infection. 
     
     
         5 . The oligonucleotide for use according to  claim 4  wherein the disease is ALT-positive cancer. 
     
     
         6 . The oligonucleotide for use according to  claim 4  wherein the cancer is selected from the group consisting of: soft tissue sarcoma, preferably chondrosarcoma, undifferentiated pleomorphic sarcomas including malignant fibrous histiocytoma, leiomyosarcoma, epithelioid sarcoma, liposarcoma, fibrosarcoma and variants, angiosarcoma and neurofibroma, central nervous system cancer, preferably grade 2 diffuse astrocytoma; grade 3 anaplastic astrocytoma; grade 4 paediatric glioblastoma multiforme, oligodendroglioma, anaplastic medulloblastoma, grade 1 pilocytic astrocytoma, nonanaplastic medulloblastoma, meningioma, schwannoma, urinary bladder cancer, in particular small cell carcinoma and invasive urothelial carcinoma, adrenal gland or peripheral nervous system cancer, in particular ganglioneurobalstoma, neuroblastoma and pheochromocytoma, neuroendocrine neoplasms such as paraganglioma and carcinoid tumour, kidney cancer, in particular chromophobe carcinoma, sarcomatoid carcinoma and clear cell and papillary carcinomas, lung and pleural cancer, in particular malignant mesothelioma, large cell carcinoma and small cell carcinoma, skin cancer such as malignant melanoma, liver cancer such as hepatocellular carcinoma, testis cancer such as non seminomatous germ cell tumor, breast cancer, in particular lobular carcinoma; ductal carcinoma and medullary carcinoma, uterus cancer such as serous endometrial carcinoma, squamous carcinoma of cervix, ovary cancer, in particular clear cell carcinoma, endometrioid carcinoma, Gall bladder cancer such as adenocarcinoma, oesophagus cancer. 
     
     
         7 . An oligonucleotide comprising at least one of the following sequences:
 (TTAGGG) SEQ ID No. 1, (TAGGGT) SEQ ID No. 2, (AGGGTT) SEQ ID No. 3, (GGGTTA) SEQ ID No. 4, (GGTTAG) SEQ ID No. 5 or (GTTAGG) SEQ ID No. 6 or a complementary sequence thereof or a variant or a mixture thereof for use in the treatment and/or prevention of a non-cancer condition associated with telomere dysfunction wherein the variant comprises one of the following sequence: TCAGGG, TTCGGG, GTAGGG, TGAGGG, TTGGGG, TAAGGG, ATAGGG, CTAGGG, TTTGGG or TTAAGGG.   
     
     
         8 . The oligonucleotide or a complementary sequence thereof or a variant thereof for use according to  claim 7  comprising at least one of the following sequences: (TTAGGG) n , (TAGGGT), (AGGGTT) n , (GGGTTA) n , (GGTTAG) n  or (GTTAGG) n  wherein 1<n<1000, preferably 1<n<500, preferably 1<n<200, preferably 1<n<100, preferably 1<n<50, preferably 1<n<20, preferably 1<n<10, preferably 1<n<5. 
     
     
         9 . The oligonucleotide for use according to  claim 7  wherein the non-cancer condition associated with telomere dysfunction is selected from the group consisting of: Hutchinson-Gilford progeria syndrome (HGPS), Werner's syndrome, Bloom's syndrome, ataxia telangiectasia, familial IPF, sporadic IPF, aplastic anaemia, autosomal-dominant dyskeratosis congenital, Familial MDS-AML, de novo dyskeratosis congenita, X-linked recessive dyskeratosis congenita, Hoyeraal-Hreiderasson syndrome, Revesz syndrome, Autosomal-recessive dyskeratosis congenita, Coats plus syndrome, condition caused by mutations or inactivation of any one of TRF 1, POT 1, TPP 1, TINF2, RAP 1 or TRF2, impaired regeneration upon partial hepatectomy, liver fibrosis, liver Chronic inflammation, liver cirrhosis, pulmonary fibrosis, altered myeloid progenitor differentiation, bone marrow failure, chronic obstructive pulmonary disease (COPD), neurological disorders including Alzheimer's Disease, osteoporosis, atherosclerosis, heart disease, Duchenne muscular dystrophy, Type 2 diabetes, impaired fertility, impaired wound healing, arthritis, cataracts, age-related macular degeneration, ageing. 
     
     
         10 . The oligonucleotide for use according to  claim 1  being a locked nucleic acid (LNA)-modified oligonucleotide, a 2′-O-Methyl-modified oligonucleotide, a phosphorothioate modified oligonucleotide, a phosphorothioate modified locked nucleic acid, a 2′-O-methoxyethyl modified oligonucleotide, a 20-[2-(N-Methylcarbamoyl)ethyl] ribonucleoside, a methylphosphonate, a morpholino oligonucleotide, a LNA-DNA-LNA gapmer oligonucleotide, a mixmer, a Chimeric 2′-O-methyl RNA-DNA gapmer, a N3′-P5′ Phosphoroamidate, a 2′-fluoro-arabino nucleic acid, a Phosphoroamidate Morpholino, Cyclohexene nucleic acid, a Tricyclo-DNA, a Peptide nucleic acid, an Unlocked nucleic acid, a Hexitol nucleic acid, a Boranophosphate oligonucleotide, a Phosphoroamidate oligonucleotide, preferably said modified oligonucleotide is phosphorothioated. 
     
     
         11 . A pharmaceutical composition comprising at least one oligonucleotide as defined in  claim 1  and pharmaceutically acceptable carriers for use in the treatment and/or prevention of a disease characterized by alternative lengthening of telomeres or for use in the treatment and/or prevention of a non-cancer condition associated with telomere dysfunction. 
     
     
         12 . The pharmaceutical composition for use according to  claim 11  further comprising at least one other therapeutic agent, preferably the other therapeutic agent is an anti-tumoral agent, an anti-pain agent or an anti-emetic agent. 
     
     
         13 . The pharmaceutical composition for use according to  claim 12  wherein the other therapeutic agent is selected from the group consisting of: ATR inhibitor, DDR inhibitor, HR inhibitor, molecule that specifically target telomeres, preferably G-quadruplexes interacting molecules, molecule that cause DNA damage generation at telomeres.