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(12) Patent Application Publication (10) Pub. No.: US 2015/0284724 A1 COLLARD Et Al US 20150284724A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0284724 A1 COLLARD et al. (43) Pub. Date: Oct. 8, 2015 (54) TREATMENT OF SIRTUIN (SIRT) RELATED (60) Provisional application No. 61/330,427, filed on May DISEASES BY INHIBITION OF NATURAL 3, 2010, provisional application No. 61/415,891, filed ANTISENSE TRANSCRIPT TO A SIRTUN on Nov. 22, 2010, provisional application No. 61/412, (SIRT) 066, filed on Nov. 10, 2010, provisional application No. 61/409,136, filed on Nov. 2, 2010. (71) Applicant: CuRNA, Inc., Miami, FL (US) Publication Classification (72) Inventors: Joseph COLLARD, Delray Beach, FL (US): Olga Khorkova Sherman, (51) Int. Cl. Tequesta, FL (US); Carlos Coito, West CI2N IS/II3 (2006.01) Palm Beach, FL (US); Belinda De Leon, (52) U.S. Cl. San Francisco, CA (US) CPC ........ CI2N 15/1137 (2013.01); C12N 2310/11 (2013.01) (21) Appl. No.: 14/741,164 (57) ABSTRACT (22) Filed: Jun. 16, 2015 The present invention relates to antisense oligonucleotide that modulate the expression of and/or function of a Sirtuin Related U.S. ApplicationO O Data RidSIRT), in particular,p a Sirtuin by Rs. targeting E. inventionnatural antisense also ria poly o (62) Division of application No. 13/695,801, filed on Nov. the identification of these antisense oligonucleotides and their 2, 2012, now Pat. No. 9,089,588, filed as application use in treating diseases and disorders associated with the No. PCT/US2011/021052 on Jan. 13, 2011. expression of Sirtuins (SIRT)s. Patent Application Publication Oct. 8, 2015 Sheet 1 of 14 US 2015/0284724 A1 F}, i Foid tiererica in SiRi expression after treatnerit with siris to Sas c. : 3 3 38 s s 3. S. a S 6 8 S s s: 3 $ 3. 3. S 3 in FC Fesix difference in sistas expressics after treatment with risis. As it sittas sirt:S stasis stas 7 Patent Application Publication Oct. 8, 2015 Sheet 2 of 14 US 2015/0284724 A1 FORE fascichsage is SRii in NA copyriter cigared to inactive gastroi S.S. iss. a r, E. & c 8. w . S S. S. : : S S. S. & S FRS, fed cišerences in SERS3 expy stribef extirpassex to costs at s38. -, CF33S.S. R& sit: 8x2-i-Sika £f &S sit 2-2 six 28& 2-g- a 3-Rsraethy: : NAS is:ytrix 8.85 {R-073: Ri888 R&G R-86s. R.3863 Patent Application Publication Oct. 8, 2015 Sheet 3 of 14 US 2015/0284724 A1 FORES *aid difference in SRT1 copy narrater copared its to stre: P:3, FSS: E S3R S-3 RS &E RHS sirt 232 SA; FORS is Fair silifferees it SRS rRNA agy is nies Enjaared to antic 3. s ..S. 3.8. 8. 33-33 Patent Application Publication Oct. 8, 2015 Sheet 4 of 14 US 2015/0284724 A1 F.R. $oid difference in SRf 38A togy auxixe afief treatsyer twis &liga assist SSSR as cared to contra: FSS SiR'S FORS 8 six difference is fia &ay reber ergaret Ra cates: SPS, SER: Patent Application Publication Oct. 8, 2015 Sheet 5 of 14 US 2015/0284724 A1 F; ; *oid difference it trii copy is earnga red to contro st: R&:8: S$8 , i ERE * if:eese is is NA gy & E::paredits kit S8. S. g s& r K w es s s s: & Patent Application Publication Oct. 8, 2015 Sheet 6 of 14 US 2015/0284724 A1 GRE Foix difference in RNA copy it corp3.res to centra E.8 :S ; P: . P: SES . i. & .2 s w 3,3 3:3S & 8 88. s s as r r wr e ck : : . RE Feist difference it rRNA copy nutrier &cipated to controi Sii Pa,3 s s: e8 r ss s r r r s r 8. s e s Patent Application Publication Oct. 8, 2015 Sheet 7 of 14 US 2015/0284724 A1 GRE 3 Foid difference in rRNA copy is cargaret to cartrai C?8-949 CR-3 (3R,3398 (C38.895 GRE : Saša diffence in 388 copy is catgage to carts a . r. S3S 3: & s :s s 3.: E. s s E. S. s & R n Patent Application Publication Oct. 8, 2015 Sheet 8 of 14 US 2015/0284724 A1 G RES Faiti charge in rary Accrgy if consisteritis entre: SSR i FERE 6 raid charge cars pared to tetroi Patent Application Publication Oct. 8, 2015 Sheet 9 of 14 US 2015/0284724 A1 FEG RE Fox: diffee-tie in 188s cog furtier co: 3:3 to cotti: FRE 8 sis iss'ssE. E 1-, &SSS3 S’s & Patent Application Publication Oct. 8, 2015 Sheet 10 of 14 US 2015/0284724 A1 RE is: 888&ss is sis GRE 20 Sets: riffssc; ii. 888 is is arris's to ris: $8. ... .333 S$33. SERS Patent Application Publication Oct. 8, 2015 Sheet 11 of 14 US 2015/0284724 A1 EE SS: RE 13 Se:cess eS-8.2.xy S is is 3,83S w S. FORE 23 Fate sixsness is 88.5 tasy & sateix.88 to exers: R 8', six& SSS $538. 3.SSS: Patent Application Publication Oct. 8, 2015 Sheet 12 of 14 US 2015/0284724 A1 GRE Ficifere's: its RNA tepsy is taxas a circa . S. 8 0.4 -88s -88 B-ESS RSS RS-8S R-SS RES exici differe see in 8NA copy icoparsi to crite: & SS 3. S.S. S E838. 3. SS. 35. Patent Application Publication Oct. 8, 2015 Sheet 13 of 14 US 2015/0284724 A1 GRE 6 Foid iii.feretes in nin.A copy # exparse to tertrai iS$82, RE said tieressee irs RN& copy crispated to entras 3:SSS S. $$$$$. Šs SSS Patent Application Publication Oct. 8, 2015 Sheet 14 of 14 US 2015/0284724 A1 GRES fixis sifs:’sses is issSNF, issy is : Yiyskies 3& Six: x} FORE 2 Scies &ifiesses r &&.8, copy: star: ix cists sis w 83.33. E.E., US 2015/0284724 A1 Oct. 8, 2015 TREATMENT OF SIRTUIN (SIRT) RELATED 0006. In another embodiment, an oligonucleotide targets a DISEASES BY INHIBITION OF NATURAL natural antisense sequence of a Sirtuin (SIRT) polynucle ANTISENSE TRANSCRIPT TO A SIRTUN otide, for example, nucleotides set forth in SEQID NO: 9 to (SIRT) 23, 141 to 143, and any variants, alleles, homology, mutants, derivatives, fragments and complementary sequences FIELD OF THE INVENTION thereto. Examples of antisense oligonucleotides useful in practicing the methods of the present invention are set forth as 0001. The present application claims the priority of U.S. SEQID NOS: 24 to 127. provisional patent application No. 61/330,427 filed May 3, 0007 Another embodiment provides a method of modu 2010, U.S. provisional patent application No. 61/409,136 lating function and/or expression of a Sirtuin (SIRT) poly filed Nov 2, 2010, U.S. provisional patent application No. nucleotide in patient cells or tissues in Vivo or in vitro com 61/412,066 filed Nov. 10, 2010 and U.S. provisional patent prising contacting said cells or tissues with an antisense application No. 61/415,891 filed Nov. 22, 2010. oligonucleotide 5 to 30 nucleotides in length wherein said 0002 Embodiments of the invention comprise oligonucle oligonucleotide has at least 50% sequence identity to a otides modulating expression and/or function of a Sirtuin reverse complement of an antisense of the Sirtuin (SIRT) (SIRT) and associated molecules. polynucleotide; thereby modulating function and/or expres sion of the Sirtuin (SIRT) polynucleotide in patient cells or BACKGROUND tissues is vivo or in vitro. 0008 Another embodiment provides a method of modu 0003 DNA-RNA and RNA-RNA hybridization are lating function and/or expression of a Sirtuin (SIRT) poly important to many aspects of nucleic acid function including nucleotide in patient cells or tissues in Vivo or in vitro com DNA replication, transcription, and translation. Hybridiza prising contacting said cells or tissues with an antisense tion is also central to a variety of technologies that either oligonucleotide 5 to 30 nucleotides in length wherein said detect a particular nucleic acid or alter its expression. Anti oligonucleotide has at least 50% sequence identity to an anti sense nucleotides, for example, disrupt gene expression by sense oligonucleotide to a Sirtuin (SIRT) antisense poly hybridizing to target RNA, thereby interfering with RNA nucleotide; thereby modulating function and/or expression of splicing, transcription, translation, and replication. Antisense the Sirtuin (SIRT) polynucleotide in patient cells or tissues in DNA has the added feature that DNA-RNA hybrids serve as vivo or in vitro. a substrate for digestion by ribonuclease H, an activity that is 0009. In one embodiment, a composition comprises one or present in most cell types. Antisense molecules can be deliv more antisense oligonucleotides which bind to sense and/or ered into cells, as is the case for oligodeoxynucleotides antisense Sirtuin (SIRT) polynucleotides. (ODNs), or they can be expressed from endogenous genes as 0010. In another embodiment, the oligonucleotides com RNA molecules. The FDA recently approved an antisense prise one or more modified or substituted nucleotides. drug, VITRAVENETM (for treatment of cytomegalovirus 0011. In another embodiment, the oligonucleotides com retinitis), reflecting that antisense has therapeutic utility. prise one or more modified bonds. 0012. In yet another embodiment, the modified nucle SUMMARY otides comprise modified bases comprising phosphorothio 0004. In one embodiment, the invention provides methods ate, methylphosphonate, peptide nucleic acids, 2'-O-methyl, for inhibiting the action of a natural antisense transcript by flouro- or carbon, methylene or other locked nucleic acid using antisense oligonucleotide(s) targeted to any region of (LNA) molecules.
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