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(12) Patent Application Publication (10) Pub. No.: US 2012/0322991 A1 Montefeltro Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2012/0322991 A1 Montefeltro Et Al US 2012O322991A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2012/0322991 A1 Montefeltro et al. (43) Pub. Date: Dec. 20, 2012 (54) COMPOSITIONS AND METHODS FOR (30) Foreign Application Priority Data SELECTIVE DELIVERY OF OLGONUCLEOTDE MOLECULESTO Apr. 19, 2010 (EP) .............................. EP10382O87.4 SPECIFIC NEURON TYPES Feb. 9, 2011 (EP) .............................. EP11382O31.0 (75) Inventors: Andres Pablo Montefeltro, Barcelona Publication Classification (ES); Gabriel Alvarado Urbina, 51) int. C Nepean (CA); Analia Bortolozzi (51) Ot 21/00 (2006.01) Biassoni, Barcelona (ES); Francesc (52) U.S. Cl 536/23.1 Artigas Perez, Barcelona (ES); Miquel Oa - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Vila Bover, Barcelona (ES) (57) ABSTRACT The invention provides a conjugate comprising (i) a nucleic (73) Assignee: NLIFE THERAPEUTICS, S.L., La acid which is complementary to a target nucleic acid Coruna (ES) sequence and which expression prevents or reduces expres sion of the target nucleic acid and (ii) a selectivity agent which (21) Appl. No.: 13/066,590 is capable of binding with high affinity to a neurotransmitter 1-1. transporter. The conjugates of the present invention are useful (22) Filed: Apr. 19, 2011 for the delivery of the nucleic acid to a cell of interests and O O thus, for the treatment of diseases which require a down Related U.S. Application Data regulation of the protein encoded by the target nucleic acid as (60) Provisional application No. 61/325,515, filed on Apr. well as for the delivery of imaging agents to the cells for 19, 2010. diagnostic purposes. Patent Application Publication Dec. 20, 2012 Sheet 1 of 18 US 2012/0322991 A1 y 8-OH-DPAT 1 mg/kg i.p., 24 h after siRNA infusion 1 --O-- Vehicle Dg 9 ----------" -o- ns naked siRNA s W - T ------arr O O >< A at---- -m--As- nS NLF-SiRNA-si -- 1 - - -- - ---- naked 5-HTAR-siRNAA. 3. -1- W* * ?is?/.5 --A-5-HT1AR-NLF-siRNA8 U. S. --O-- 5-HTAR-KO O 30 60 90 120 Time (min) FIG. 1 Dorsal raphe nucleus 5O OVehicle oS 40 nS naked siRNA 5 g Ens. NLF-siRNA 5 30 naked 5-HTAR-siRNA s g 20 5-HTAR-NLF-siRNA S O 5 O O Patent Application Publication Dec. 20, 2012 Sheet 2 of 18 US 2012/0322991 A1 *****g **********************************$ 88. 3. Patent Application Publication Dec. 20, 2012 Sheet 3 of 18 US 2012/0322991 A1 A) Dorsal raphe nucleus : OVehicle ns naked siRNA 2O Eris NF-siRNA 1030 naked 5-HTAR-siRNA 5-HTAR-NLF-siRNA . o B) 7O Prefrontal Cortex O C ) 70 Hi p p O C 3. r O U S . sO Patent Application Publication Dec. 20, 2012 Sheet 4 of 18 US 2012/0322991 A1 A) Dorsal raphe nucleus 300 Vehicle ns naked siRNA Ens NLF-siRNA naked 5-HTAR-siRNA 5-HTAR-NLF-siRNA B) 1 5 O O FG. 5 Patent Application Publication Dec. 20, 2012 Sheet 5 of 18 US 2012/0322991 A1 y 8-OH-DPAT 1 mg/kg i.p., 24 h after siRNA infusion D --O-- Vehicle O SS --O-- ns naked siRNA O S --Arns NLF-SiRNA 8 ---- naked 5-HTAR-siRNA g --A-, 5-HT1AR-NLF-siRNA E -o-, 5-HTAR KO U 9 O 30 60 90 120 Time (min) FIG. 6 Prefrontal Cortex 7s 'l 8-OH-DPAT 0.5 mg/kg i.p. 1OO w S r s an: -O-Vehicle & 50 al - A - ns NLF-siRNA -a-5-HTAR-NLF-siRNA -o-5-HTAR-KO Patent Application Publication Dec. 20, 2012 Sheet 6 of 18 US 2012/0322991 A1 s 3: 8: 8: 8:: i8 in ::... 8 Patent Application Publication Dec. 20, 2012 Sheet 7 of 18 US 2012/0322991 A1 Prefrontal Cortex 500 () E: 400 Fluoxetine 20 mg/kg i.p. 300 200 "-o-Vehicle 9. - A - nS NLF-siRNA 100+---air....7. -A-5-HTAR-NLF-siRNA -o-, 5-HTAR-KO FG, 9 Patent Application Publication Dec. 20, 2012 Sheet 8 of 18 US 2012/0322991 A1 A) Elevated plus-maze 40 re S -- s E -- V 30 () 3. 3. 9 n E E 10 S. S s O B) Tail suspension test 160 Vehicle - 1 2O - 5-HTAR-NLF-siRNA 5-HTAR-KO 4080 FG, 10 Patent Application Publication Dec. 20, 2012 Sheet 9 of 18 US 2012/0322991 A1 A) B) Dorsal raphe nucleus 7 s g i e 9 st 6 al g s 2 OVehicle 8 th E 1 Ens NLF-siRNA s 5-HTAR-NLF-siRNA C) Prefrontal cortex D) Hippocampus 70 S6 o 89 so gig9 is a 40 is a 4 SS330 a 5230 is 20 g 20 So E 10 O FIG 11 Patent Application Publication Dec. 20, 2012 Sheet 10 of 18 US 2012/0322991 A1 A) v 8-OH-DPAT 1 mg/kg i.p., 24 h after siRNA infusion S 1 3 c) e 8g 3. - -O-Vehicle -2 - A - nS NLF-SiRNA O S. -A-5-HTAR-NLF-siRNA -3 O 30 60 90 120 Time (min) B) Prefrontal COrtex 150 8-OH-DPAT 0.5 mg/kg i.p. 50 Patent Application Publication Dec. 20, 2012 Sheet 11 of 18 US 2012/0322991 A1 *x: Eiewated pius-taxe : 3. :- : : ik gir. 8. Tail suspension test : 3 Patent Application Publication Dec. 20, 2012 Sheet 12 of 18 US 2012/0322991 A1 C) Forced SWim Test 200 N-160 C) E 120 e as 80 2 40 E ol 0-2 2-4 4-6 0-6 Time blocks (min) Vehicle 5-HTA-NLF-siRNA 100 ug FIG. 13 (cont.) Patent Application Publication Dec. 20, 2012 Sheet 13 of 18 US 2012/0322991 A1 A) 8. & 3.x: :388:38: x. ; :::::: *********3.****** teroidea4,3%}{{C} ::::::: Patent Application Publication Dec. 20, 2012 Sheet 14 of 18 US 2012/0322991 A1 **** :8. $8. Patent Application Publication Dec. 20, 2012 Sheet 15 of 18 US 2012/0322991 A1 A) Dorsal striatum 2 5O Fluoxetine 20 mg/kg i.p. 2 O O 1 5 O 1 O O 5 O -- 5-HTNLF-SiRNA 10 -A-5-HTNLF-SiRNA 30 O B) 500 4O O Cit 10 M 3O O t 2O O 1 OO FG 16 Patent Application Publication Dec. 20, 2012 Sheet 16 of 18 US 2012/0322991 A1 C D F.G. 17 Patent Application Publication Dec. 20, 2012 Sheet 17 of 18 US 2012/0322991 A1 FIG, 18 Patent Application Publication Dec. 20, 2012 Sheet 18 of 18 US 2012/0322991 A1 YOYO-1-ir Cy3-ir Overlap FIG. 19 US 2012/0322991 A1 Dec. 20, 2012 COMPOSITIONS AND METHODS FOR fering molecules. For instance, Kumar et al. (Nature, 2007, SELECTIVE DELIVERY OF 448:39-44) have described conjugates of siRNA and a pep OLGONUCLEOTDE MOLECULESTO tide derived from the rabies virus glycoprotein comprising a SPECIFIC NEURON TYPES nonamer arginine and their ability to silence gene expression in the brain after intravenous injection. Xia et al. (Pharma RELATED APPLICATIONS ceutical Research, 2007, 24:2309-2316) have described con jugates comprising a biotinylated siRNA and a conjugate 0001. This application claims priority benefit of U.S. Pro comprising avidin-anti-transferrin receptor antibody which visional Application 61/325,515 filed 19 Apr. 2010; European are capable of silencing gene expression in the central ner Patent Application EP10382087.4 filed 19 Apr. 2010; and vous system after systemic delivery. WO200979790 describe European Patent Application EP 11382031.0 filed 9 Feb. conjugates comprising siRNA and a series of peptides collec 2010; these applications are hereby incorporated by refer tively known as Angiopeps which are capable of crossing the CCC. blood-brain barrier by receptor-mediated transcytosis using the low-density lipoprotein receptor-related protein-1 (LRP FIELD OF THE INVENTION 1) and which allows the delivery to the CNS of systemically 0002 The present invention relates to conjugates compris administered conjugates comprising said peptides. ing a nucleic acid specific for a target of interest and a group WO2007 107789 describes the use of compounds capable of which allows the delivery of the nucleic acids to specific cells causing RNA interference and which are specific for targets within the central nervous system by means of their affinity present in the CNS and the delivery to the CNS by the use of towards neurotransmitter transporter molecules on the Sur intranasal administration. face of said cells. 0006. However, while all these systems allow the delivery of systemically administered siRNAs to the CNS, they do not BACKGROUND ART allow delivery to specific cell types within the brain. In fact, 0003. The use of nucleic acids has proved effective for no delivery system has been described to date which allows altering the state of a cell. The introduction of deoxyribo delivery of atherapeutic agent to a specific cell type within the nucleic acid (DNA) or ribonucleic acid (RNA) into a cell can CNS. The possibility of delivering siRNAs of known speci be used to up- or down-regulate the expression of particular ficity to the central nervous system will be usesful for the genes in the cell, thereby, impacting one or more biochemical treatment of diseases which are caused by an undesired activ pathways. Of the nucleic acid-based technologies used to ity/expression of a given gene, including depression, cogni alter cell physiology, RNA interference (RNAi) is the general tive disorders, Parkinson's disease, Alzheimer's disease, etc. term given for regulating the expression of genes at the post 0007 Depression is recognized as a disease of the central transcriptional level in diversified organisms. RNAi gene nervous system. Depression is both biologically and geneti silencing can be accomplished using homologous short (21 cally a heterogeneous disorder, with symptoms manifested at 23 bp) dsRNA fragments known as short interfering or the psychological, behavioural and physiological level.
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