# US 2019/0055561 A1 · Micro-rnas and compositions comprising same for the treatment and diagnosis of serotonin-, adrenalin-, noradrenalin-, glutamate-, and corticotropin-releasing hormone- associated medical conditions

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- Number: US 2019/0055561 A1
- Document ID: US20190055561A1
- Status: Published application
- Kind: A1
- Application number: 16/180,083
- Filed: 2018-11-05
- Published: 2019-02-21
- Earliest claimed: 2014-02-05
- Assignees: Yeda Research and Development Co. Ltd.
- Applicants: Yeda Research and Development Co. Ltd.
- Inventors: Alon CHEN; Orna ISSLER
- Web page: https://patentgrep.com/patent/US20190055561A1

## CPC

- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- A61P 15/10: for impotence
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- A61P 25/20: Hypnotics; Sedatives
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 25/30: for treating abuse or dependence
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12Q 1/6883: for diseases caused by alterations of genetic material
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2320/30: Special therapeutic applications
- C12Q 2600/158: Expression markers
- C12Q 2600/178: miRNA, siRNA or ncRNA
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES

## Abstract

A method of treating a bipolar disorder in a subject in need thereof is disclosed. The method comprising administering to the subject sa therapeutically effective amount of a miR-135, a precursor thereof or a nucleic acid molecule encoding said miR-135 or said precursor thereof, thereby treating the bipolar disorder. Methods of diagnosing a mood disorder in a human subject and of monitoring treatment of an anti-depressant drug or a medicament for the treatment of a mood disorder are also disclosed.

## Claims

### Claim 1

A method of monitoring treatment of an anti-depressant drug or a medicament for the treatment of a mood disorder, the method comprising:
(a) treating a human subject in need thereof with an anti-depressant drug or a medicament for the treatment of a mood disorder; and
(b) measuring an expression level of a miR-135 in biological sample of said human subject prior to and following said treatment, wherein a higher expression level of said miR-135 following said treatment by said anti-depressant drug or said medicament for said treatment of said mood disorder as compared to said expression level of said miR-135 prior to said treatment by said anti-depressant drug or said medicament for said treatment of said mood disorder is indicative of the efficient treatment.

### Claim 2 (depends on 1)

The method of claim 1, further comprising (c) treating the human subject when a higher expression level of said miR-135 is observed in step (b).

### Claim 3 (depends on 1)

The method of claim 1, further comprising obtaining a biological sample from said human subject prior to said treating.

### Claim 4 (depends on 1)

The method of claim 1, wherein said biological sample is selected from the group consisting of a whole blood, a serum, a plasma and white blood cells.

### Claim 5 (depends on 1)

The method of claim 1, wherein said mood disorder comprises a bipolar disorder.

### Claim 6 (depends on 1)

The method of claim 1, wherein said anti-depressant drug is selected from the group consisting of selective serotonin reuptake inhibitors (SSRI), tricyclic antidepressants and noradrenaline reuptake inhibitors (NRI).

### Claim 7 (depends on 1)

The method of claim 1, wherein said medicament for said treatment of said mood disorder is selected from the group consisting of a lithium, an antipsychotic medicament and a mood stabilizer medicament.

### Claim 8

A method of diagnosing a mood disorder in a human subject in need thereof, the method comprising measuring an expression level of a miR-135 in a biological sample of the human subject, wherein a lower expression level of said miR-135 as compared to that in a biological sample of a healthy human subject is indicative of the mood disorder.

### Claim 9 (depends on 8)

The method of claim 8, wherein said biological sample is selected from the group consisting of a whole blood, a serum, a plasma and white blood cells.

### Claim 10 (depends on 8)

The method of claim 8, wherein said mood disorder is selected from the group consisting of a bipolar disorder, a depression, a major depression, an anxiety, a stress, a fatigue, an impaired cognitive function, a panic attack, a compulsive behavior, an addiction, a social phobia, a schizophrenia, a sleep disorder and an eating disorder.

### Claim 11 (depends on 8)

The method of claim 8, wherein said miR-135 is selected from the group consisting of miR-135a or miR-135b.

### Claim 12

A method of downregulating an expression of a gene selected from the group consisting of adenylate cyclase activating polypeptide 1 (Adcyap1 or PACAP); adenylate cyclase activating polypeptide 1 receptor 1 (Adcyap1r1); adrenergic receptor, alpha 2a (Adra2a); an ankyrin 3 (ANK3); activity-regulated cytoskeleton-associated protein (Arc); Rho GTPase activating protein 6 (Arhgap6); activating transcription factor 3 (Atf3); beta-site APP cleaving enzyme 1 (Bace1); calcium channel, voltage-dependent, L type, alpha 1D subunit (Cacna1d); cell adhesion molecule 3 (Cadm3); complexin 1 (Cplx1); complexin 2 (Cplx2); CUB and Sushi multiple domains 1 (Csmd1); casein kinase 1, gamma 1 (Csnk1g1); doublecortin (Dcx); DIRAS family, GTP-binding RAS-like 2 (Diras2); discs, large homolog 2 (Drosophila) (Dlg2); ELK1, member of ETS oncogene family (Elk1); fyn-related kinase (Frk); fucosyltransferase 9 (alpha (1,3) fucosyltransferase) (Fut9); gamma-aminobutyric acid (GABA-A) receptor, subunit beta 2 (Gabrb2); GATA binding protein 3 (Gata3); growth hormone secretagogue receptor (Ghsr); G protein-coupled receptor 3 (Gpr3); a glutamate receptor, ionotropic AMPA3 (alpha 3) (GRIA3); glutamate receptor, ionotropic, kainate 3 (Grik3); G protein-coupled receptor kinase 5 (Grk5); a glycogen synthase kinase-3beta (GSK3B); hyperpolarization activated cyclic nucleotide-gated potassium channel 1 (Hcn1), hyperpolarization-activated, cyclic nucleotide-gated K+2 (Hcn2), 5-hydroxytryptamine (serotonin) receptor 1A (Htr1a); inositol monophosphatase (IMPA1), kalirin, RhoGEF kinase (Kalrn); a potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 (KCNN3); karyopherin alpha 3 (importin alpha 4) (Kpna3); myelin transcription factor 1-like (Myt11); nuclear receptor coactivator 2 (Ncoa2); N-Myc Downstream-Regulated Gene 4 (Ndrg4); a nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP); nuclear receptor subfamily 3, group C, member 2 (Nr3c2); netrin G1 (Ntng1); nuclear casein kinase and cyclin-dependent kinase substrate 1 (Nucks1); phosphodiesterase 1A, calmodulin-dependent (Pde1a); phosphodiesterase 4A, cAMP specific (Pde4a); phosphodiesterase 8B (Pde8b); phospholipase C, beta 1 (Plcb1); prolactin receptor (Prlr); RAB1B, member RAS oncogene family (Rab1b); Ras-Related Protein Rap-2a (Rap2a); Retinoid-Related Orphan Receptor Beta (Rorb); sirtuin 1 (silent mating type information regulation 2, homolog) 1 (Sirt1); solute carrier family 12, (potassium/chloride transporters) member 6 (Slc12a6); solute carrier family 5 (choline transporter), member 7 (Slc5a7); solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4); trans-acting transcription factor 1 (Sp1); synaptic vesicle glycoprotein 2 b (Sv2b); Synaptic nuclear envelope 1 (encodes nesprin-1) (Syne1); synaptotagmin I (Syt1); synaptotagmin II (Syt2); synaptotagmin III (Syt3); transforming growth factor, beta receptor II (Tgfbr2); thyroid hormone receptor, beta (Thrb); transient receptor potential cation channel, subfamily C, member 6 (Trpc6); vesicle-associated membrane protein 2 (Vamp2); wingless-related MMTV integration site 3 (Wnt3); and zinc finger, BED domain containing 4 (Zbed4) in a neuroglia cell, the method comprising:
(a) upregulating an activity or expression of a miR-135 or a precursor thereof in said neuroglia cell; and
(b) measuring an expression of said gene in said neuroglia cell,
thereby downregulating the expression of the gene.

### Claim 13 (depends on 12)

The method of claim 12, wherein said upregulating said activity or expression of said miR-135 is effected by administering to said neuroglia cell a miR-135, a precursor thereof, or a polynucleotide encoding said miR-135 or said precursor thereof.

### Claim 14 (depends on 12)

The method of claim 12, wherein said miR-135 is selected from the group consisting of miR-135a and miR-135b.

### Claim 15 (depends on 12)

The method of claim 12, wherein said miR-135 is as set forth in SEQ ID NO: 58-62.

### Claim 16 (depends on 12)

The method of claim 12, wherein said miR-135 comprises miR-135* as set forth in SEQ ID NO: 192-193.

### Claim 17 (depends on 12)

The method of claim 12, wherein said miR-135 comprises a modification selected from the group consisting of a modified sugar-phosphate backbone and a modified base.

### Claim 18 (depends on 12)

The method of claim 12, wherein said miR-135 comprises a modification in both a sugar and an internucleoside linkage.

### Claim 19 (depends on 18)

The method of claim 18, wherein said modification is selected from the group consisting of a phosphorothioate, a chiral phosphorothioate, a phosphorodithioate, a phosphotriester, an aminoalkyl phosphotriester, a methyl phosphonate, an alkyl phosphonate, a chiral phosphonate, a phosphinate, a phosphoramidate, an aminoalkylphosphoramidate, a thionophosphoramidate, a thionoalkylphosphonate, a thionoalkylphosphotriester, a boranophosphate, a phosphodiester, a 2′-O-methoxyethyl, a 2′-O-methyl, a 2′-fluoro, a locked nucleic acid (LNA), a peptide nucleic acid (PNA) and a 2′-Fluoroarabinooligonucleotides (FANA).

### Claim 20 (depends on 18)

The method of claim 18, wherein said miR-135 is as set forth in SEQ ID NO: 194-209.

### Claim 21 (depends on 12)

A method of treating a subject in need thereof, the method comprising administering to the subject the neuroglia cell of claim 12.

### Claim 22 (depends on 21)

The method of claim 21, wherein said subject suffers from a medical condition selected from the group consisting of a bipolar disorder, a depression, a major depression, an anxiety, a stress, a fatigue, an impaired cognitive function, a panic attack, a compulsive behavior, an addiction, a social phobia, a schizophrenia, a sleep disorder, an eating disorder, a growth disorder and a reproduction disorder.

### Claim 23

A method of treating a medical condition in which an elevation of serotonin level is therapeutically beneficial in a subject in need thereof, the method comprising administering to the subject an agent capable of downregulating an activity or expression of a miR-135 target selected from the group consisting of adenylate cyclase activating polypeptide 1 (Adcyap1 or PACAP); adenylate cyclase activating polypeptide 1 receptor 1 (Adcyap1r1); adrenergic receptor, alpha 2a (Adra2a); an ankyrin 3 (ANK3); activity-regulated cytoskeleton-associated protein (Arc); Rho GTPase activating protein 6 (Arhgap6); activating transcription factor 3 (Atf3); beta-site APP cleaving enzyme 1 (Bace1); calcium channel, voltage-dependent, L type, alpha 1D subunit (Cacna1d); cell adhesion molecule 3 (Cadm3); complexin 1 (Cplx1); complexin 2 (Cplx2); CUB and Sushi multiple domains 1 (Csmd1); casein kinase 1, gamma 1 (Csnk1g1); doublecortin (Dcx); DIRAS family, GTP-binding RAS-like 2 (Diras2); discs, large homolog 2 (Drosophila) (Dlg2); ELK1, member of ETS oncogene family (Elk1); fyn-related kinase (Frk); fucosyltransferase 9 (alpha (1,3) fucosyltransferase) (Fut9); gamma-aminobutyric acid (GABA-A) receptor, subunit beta 2 (Gabrb2); GATA binding protein 3 (Gata3); growth hormone secretagogue receptor (Ghsr); G protein-coupled receptor 3 (Gpr3); a glutamate receptor, ionotropic AMPA3 (alpha 3) (GRIA3); glutamate receptor, ionotropic, kainate 3 (Grik3); G protein-coupled receptor kinase 5 (Grk5); a glycogen synthase kinase-3beta (GSK3B); hyperpolarization activated cyclic nucleotide-gated potassium channel 1 (Hcn1), hyperpolarization-activated, cyclic nucleotide-gated K+2 (Hcn2), 5-hydroxytryptamine (serotonin) receptor 1A (Htr1a); inositol monophosphatase (IMPA1), kalirin, RhoGEF kinase (Kalrn); a potassium intermediate/small conductance calcium-activated channel, subfamily N, member 3 (KCNN3); karyopherin alpha 3 (importin alpha 4) (Kpna3); myelin transcription factor 1-like (Myt11); nuclear receptor coactivator 2 (Ncoa2); N-Myc Downstream-Regulated Gene 4 (Ndrg4); a nitric oxide synthase 1 (neuronal) adaptor protein (NOS1AP); nuclear receptor subfamily 3, group C, member 2 (Nr3c2); netrin G1 (Ntng1); nuclear casein kinase and cyclin-dependent kinase substrate 1 (Nucks1); phosphodiesterase 1A, calmodulin-dependent (Pde1a); phosphodiesterase 4A, cAMP specific (Pde4a); phosphodiesterase 8B (Pde8b); phospholipase C, beta 1 (Plcb1); prolactin receptor (Prlr); RAB1B, member RAS oncogene family (Rab1b); Ras-Related Protein Rap-2a (Rap2a); Retinoid-Related Orphan Receptor Beta (Rorb); sirtuin 1 (silent mating type information regulation 2, homolog) 1 (Sirt1); solute carrier family 12, (potassium/chloride transporters) member 6 (Slc12a6); solute carrier family 5 (choline transporter), member 7 (Slc5a7); solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (Slc6a4); trans-acting transcription factor 1 (Sp1); synaptic vesicle glycoprotein 2 b (Sv2b); Synaptic nuclear envelope 1 (encodes nesprin-1) (Syne1); synaptotagmin I (Syt1); synaptotagmin II (Syt2); synaptotagmin III (Syt3); transforming growth factor, beta receptor II (Tgfbr2); thyroid hormone receptor, beta (Thrb); transient receptor potential cation channel, subfamily C, member 6 (Trpc6); vesicle-associated membrane protein 2 (Vamp2); wingless-related MMTV integration site 3 (Wnt3); and zinc finger, BED domain containing 4 (Zbed4), wherein said agent is not miR-135, thereby treating the medical condition.

### Claim 24 (depends on 23)

The method of claim 23, wherein said medical condition is selected from the group consisting of a bipolar disorder, a depression, a major depression, an anxiety, a stress, a fatigue, an impaired cognitive function, a panic attack, a compulsive behavior, an addiction, a social phobia, a schizophrenia, a sleep disorder, an eating disorder, a growth disorder and a reproduction disorder.