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(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2017/019905 Al 2 February 2017 (02.02.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every A61K 48/00 (2006.01) kind of national protection available): AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, (21) International Application Number: BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, PCT/US2016/044570 DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (22) International Filing Date: HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KN, KP, KR, 28 July 2016 (28.07.2016) KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, (25) Filing Language: English PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, (26) Publication Language: English SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/198,062 28 July 2015 (28.07.2015) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: OTONOMY, INC. [US/US]; 6275 Nancy GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, Ridge Drive, SuitelOO, San Diego, California 92121 (US). TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, (72) Inventor; and DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, (71) Applicant : SARAGOVI, Horacio Uri [US/CA]; 3421 LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, Marlowe Avenue, Montreal, Quebec H4A 3L8 (CA). SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, (72) Inventor: PIU, Fabrice; 11859 Stonedale Ct., San Diego, GW, KM, ML, MR, NE, SN, TD, TG). California 9213 1 (US). Published: (74) Agent: YANG, Xiaofan; Wilson Sonsini Goodrich & Ros- — with international search report (Art. 21(3)) ati, 650 Page Mill Road, Palo Alto, California 94304 (US). [Continued on next page] (54) Title: TREATMENT USING TRUNCATED TRK B AND TRK C ANTAGONISTS (57) Abstract: Disclosed herein are ' · A methods, compositions, vectors, and kits comprising an antagonist of a trun- cated TrkC or a truncated TrkB. Also TrkC-Kin described herein are methods of treating and/or preventing an otic disease or condition associated with an elevated Tr CT I EC expression level of a truncated TrkC or truncated TrkB isoform. Fig. IB w o 2017/019905 A llll II II 11III I II III II 111 III I III II I II before the expiration of the time limit for amending the — with sequence listing part of description (Rule 5.2(a)) claims and to be republished in the event of receipt of amendments (Rule 48.2(h)) TREATMENT USING TRUNCATED TRK B AND TRK C ANTAGONISTS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 62/198,062, filed July 28, 2015, which application is incorporated herein by reference. SEQUENCE LISTING [0002] The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on July 28, 2016, is named 37173-832_601_SL.txt and is 97,604 bytes in size. BACKGROUND OF THE INVENTION [0003] Neuron loss such as sensory neuron loss is the cause of morbidity in many otic related neurodegenerative diseases. In some instances, sensory neurons express Trk family of receptors such as TrkB and/or TrkC. Activity of the Trk family of receptors correlates with sensory neuron survival or death, maintenance of synapses and phenotype, and function. SUMMARY OF THE INVENTION [0004] Disclosed herein, in certain embodiments, is a method of treating an otic disease or condition or a symptomatic or pre-symptomatic condition with alterations of otic synapses, comprising administering to a patient in need thereof a therapeutic amount of a pharmaceutical composition comprising: (a) an antagonist of truncated TrkC or truncated TrkB, wherein the antagonist induces a decrease in the truncated TrkC or truncated TrkB expression level or activity or impedes the truncated TrkC or truncated TrkB interaction with a truncated TrkC or truncated TrkB binding partner; and (b) a pharmaceutically acceptable excipient and/or a delivery vehicle. Also disclosed herein is a method of preventing an otic disease or condition or reducing the progression of an otic disease or condition, comprising administering to a patient in need thereof a therapeutic amount of a pharmaceutical composition comprising: (a) an antagonist of truncated TrkC or truncated TrkB, wherein the antagonist induces a decrease in the truncated TrkC or truncated TrkB expression level or activity or impedes the truncated TrkC or truncated TrkB interaction with a truncated TrkC or truncated TrkB binding partner; and (b) a pharmaceutically acceptable excipient and/or a delivery vehicle. In some embodiments, the otic disease or condition comprises a disease or condition associated with hearing loss. In some embodiments, the otic disease or condition comprises ototoxicity, chemotherapy induced hearing loss, excitotoxicity, sensorineural hearing loss, noise induced hearing loss, presbycusis, Meniere's Disease/Syn drome, endolymphatic hydrops, labyrinthitis, Ramsay Hunt's Syndrome, vestibular neuronitis, tinnitus, or microvascular compression syndrome. In some embodiments, the antagonist that induces a decrease in the truncated TrkC or truncated TrkB expression level or activity is a nucleic acid polymer, a polypeptide, or a small molecule. In some embodiments, the antagonist that induces a decrease in the truncated TrkC or truncated TrkB expression level or activity is a nucleic acid polymer. In some embodiments, the nucleic acid polymer hybridizes to a target sequence of the truncated TrkC or truncated TrkB mRNA. In some embodiments, the nucleic acid polymer hybridizes to a target sequence that is located at the 3'UTR region of the truncated TrkC or truncated TrkB mRNA. In some embodiments, the nucleic acid polymer hybridizes to a target sequence comprising a binding motif selected from CCAAUC, CUCCAA, or ACUGUG. In some embodiments, the nucleic acid polymer comprises a short hairpin RNA (shRNA) molecule, a microRNA (miRNA) molecule, a siRNA molecule, or a double stranded RNA molecule. In some embodiments, the nucleic acid polymer is a shRNA molecule. In some embodiments, the nucleic acid polymer comprises at least 80%, 85%, 90% , 9 5% , or 99% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-5 and 114-1 19. In some embodiments, the nucleic acid polymer comprises 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-5 and 114-1 19. In some embodiments, the nucleic acid polymer consists of a nucleic acid sequence selected from SEQ ID NOs: 1-5 and 114-1 19. In some embodiments, the nucleic acid polymer comprising at least 80%>, 85%>, 90%, 95%, or 99% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-5 hybridizes to a target sequence of the truncated TrkC. In some embodiments, the nucleic acid polymer comprising 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 1-5 hybridizes to a target sequence of the truncated TrkC. In some embodiments, the nucleic acid polymer consisting of a nucleic acid sequence selected from SEQ ID NOs: 1-5 hybridizes to a target sequence of the truncated TrkC. In some embodiments, the nucleic acid polymer comprising at least 80%>, 85%>, 90%, 95%, or 99% sequence identity to a nucleic acid sequence that hybridizes to a target sequence of the truncated TrkB. In some embodiments, the nucleic acid polymer comprising 100% sequence identity to a nucleic acid sequence that hybridizes to a target sequence of the truncated TrkB. In some embodiments, the nucleic acid polymer comprising at least 80%, 85%, 90%, 95%, or 99% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 114-1 19 hybridizes to a target sequence of the truncated TrkB. In some embodiments, the nucleic acid polymer comprising 100% sequence identity to a nucleic acid sequence selected from SEQ ID NOs: 114-1 19 hybridizes to a target sequence of the truncated TrkB. In some embodiments, the nucleic acid polymer consisting of a nucleic acid sequence selected from SEQ ID NOs: 114-1 19 hybridizes to a target sequence of the truncated TrkB. In some embodiments, the nucleic acid polymer is further modified at the nucleoside moiety, at the phosphate moiety, or a combination thereof. In some embodiments, the nucleic acid polymer further comprises one or more artificial nucleotide bases. In some embodiments, the one or more artificial nucleotide bases comprises 2'-0-methyl, 2'-0-methoxyethyl (2'-0-MOE), 2'- O-aminopropyl, 2'-deoxy, T-deoxy-2'-fluoro, 2'-0-aminopropyl (2'-0-AP), 2'-0- dimethylaminoethyl (2'-0-DMAOE), 2'-0-dimethylaminopropyl (2'-0-DMAP), T-O- dimethylaminoethyloxyethyl (2'-0-DMAEOE), or 2'-0-N-methylacetamido (2'-0-NMA) modified, locked nucleic acid (LNA), ethylene nucleic acid (ENA), peptide nucleic acid (PNA), , 5' - anhydrohexitol nucleic acids (HNA), morpholino, methylphosphonate nucleotides, thiolphosphonate nucleotides, or 2'-fluoro N3-P5'-phosphoramidites. In some embodiments, the nucleic acid polymer is at most 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, or 100 nucleotides in length. In some embodiments, the pharmaceutical composition comprising the nucleic acid polymer is administered to a patient in need thereof as an intramuscular, intratympanic, intracochlear, intravenous or subcutaneous administration.
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  • Chapter 20974

    Chapter 20974

    Genome Replication of Bacterial and Archaeal Viruses Česlovas Venclovas, Vilnius University, Vilnius, Lithuania r 2019 Elsevier Inc. All rights reserved. Glossary RNA-primed DNA replication Conventional DNA Negative sense ( À ) strand A negative-sense DNA or RNA replication used by all cellular organisms whereby a strand has a nucleotide sequence complementary to the primase synthesizes a short RNA primer with a free 3′-OH messenger RNA and cannot be directly translated into protein. group which is subsequently elongated by a DNA Positive sense (+) strand A positive sense DNA or RNA polymerase. strand has a nucleotide sequence, which is the same as that Rolling-circle DNA replication DNA replication whereby of the messenger RNA, and the RNA version of this sequence the replication initiation protein creates a nick in the circular is directly translatable into protein. double-stranded DNA and becomes covalently attached to Protein-primed DNA replication DNA replication whereby the 5′ end of the nicked strand. The free 3′-OH group at the a DNA polymerase uses the 3′-OH group provided by the nick site is then used by the DNA polymerase to synthesize specialized protein as a primer to synthesize a new DNA strand. the new strand. Genomes of Prokaryotic Viruses At present, all identified archaeal viruses have either double-stranded (ds) or single-stranded (ss) DNA genomes. Although metagenomic analyzes suggested the existence of archaeal viruses with RNA genomes, this finding remains to be substantiated. Bacterial viruses, also refered to as bacteriophages or phages for short, have either DNA or RNA genomes, including circular ssDNA, circular or linear dsDNA, linear positive-sense (+)ssRNA or segmented dsRNA (Table 1).