# US 2019/0314401 A1 · Antisense-oligonucleotides as inhibitors of tgf-r signaling

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- Number: US 2019/0314401 A1
- Document ID: US20190314401A1
- Status: Published application
- Kind: A1
- Application number: 16/442,054
- Filed: 2019-06-14
- Published: 2019-10-17
- Earliest claimed: 2014-11-16
- Assignees: NeuroVision Pharma GmbH
- Applicants: Neurovision Pharma GmbH
- Inventors: MARKUS HOSSBACH; MONIKA KRAMPERT; HANS-LOTHAR ARTH
- Web page: https://patentgrep.com/patent/US20190314401A1

## CPC

- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 11/00: Drugs for disorders of the respiratory system
- A61P 13/12: of the kidneys
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 25/16: Anti-Parkinson drugs
- A61P 25/18: Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
- 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 27/02: Ophthalmic agents
- A61P 27/16: Otologicals
- A61P 31/18: for HIV
- A61P 35/00: Antineoplastic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 39/06: Free radical scavengers or antioxidants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C12N 15/1136: {against growth factors, growth regulators, cytokines, lymphokines or hormones}
- C12N 15/1138: {against receptors or cell surface proteins}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- C12N 2310/11: Antisense
- C12N 2310/313: Phosphorodithioates
- C12N 2310/315: Phosphorothioates
- C12N 2310/3231: having an additional ring, e.g. LNA, ENA
- C12N 2310/341: Gapmers, i.e. of the type ===---===
- C12N 2310/346: having a combination of backbone and sugar modifications
- C12N 2320/30: Special therapeutic applications
- C12Y 207/1103: Receptor protein serine/threonine kinase (2.7.11.30)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES

## Abstract

The present invention relates to antisense-oligonucleotides having a length of at least 10 nucleotides, wherein at least two of the nucleotides are LNAs, their use as inhibitors of TGF-R signaling, pharmaceutical compositions containing such antisense-oligonucleotides and the use for prophylaxis and treatment of neurological, neurodegenerative, fibrotic and hyperproliferative diseases.

## Claims

### Claim at position 1

1-21. (canceled)

### Claim 22

An antisense-oligonucleotide consisting of 10 to 28 nucleotides and at least two of the 10 to 28 nucleotides are LNAs, wherein the antisense-oligonucleotide has a gapmer structure with 1 to 5 LNA units at the 3′ terminal end and 1 to 5 LNA units at the 5′ terminal end and the antisense-oligonucleotide hybridizes with a region of the gene encoding the TGF-RII or with a region of the mRNA encoding the TGF-RII, wherein the region of the gene encoding the TGF-RII or the region of the mRNA encoding the TGF-RII comprises the sequence TGGTCCATTC (Seq. ID No. 4), and the antisense-oligonucleotide comprises a sequence hybridizing with said sequence TGGTCCATTC (Seq. ID No. 4) and salts and optical isomers of said antisense-oligonucleotide, wherein the antisense-oligonucleotide inhibits the expression of TGF-RII.

### Claim 23 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the antisense-oligonucleotide hybridizes selectively only with the sequence TGGTCCATTC (Seq. ID No. 4) of the region of the gene encoding the TGF-RII or of the region of the mRNA encoding the TGF-RII.

### Claim 24 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the antisense-oligonucleotide has a length of 12 to 20 nucleotides and/or wherein the antisense-oligonucleotide has phosphate, phosphorothioate and/or phosphorodithioate as internucleotide linkages.

### Claim 25 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the antisense-oligonucleotide is represented by the following general formula (S6):
(Seq. ID No. 100)
5′-N7-AATGGACC-N8-3′
wherein
N7 represents: TGAATCTTGAATATCTCATG- (Seq. ID No. 583), GAATCTTGAATATCTCATG- (Seq. ID No. 584), AATCTTGAATATCTCATG- (Seq. ID No. 585), ATCTTGAATATCTCATG- (Seq. ID No. 586), TCTTGAATATCTCATG- (Seq. ID No. 587), CTTGAATATCTCATG- (Seq. ID No. 588), TTGAATATCTCATG- (Seq. ID No. 589), TGAATATCTCATG- (Seq. ID No. 590), GAATATCTCATG- (Seq. ID No. 591), AATATCTCATG- (Seq. ID No. 592), ATATCTCATG- (Seq. ID No. 593), TATCTCATG-, ATCTCATG-, TCTCATG-, CTCATG-, TCATG-, CATG-, ATG-, TG-, or G-; and
N8 is selected from: AGTATTCTAGAAACTCACCA, (Seq. ID No. 594), AGTATTCTAGAAACTCACC, (Seq. ID No. 595), AGTATTCTAGAAACTCAC, (Seq. ID No. 596), AGTATTCTAGAAACTCA, (Seq. ID No. 597), AGTATTCTAGAAACTC, (Seq. ID No. 598), AGTATTCTAGAAACT, (Seq. ID No. 599), AGTATTCTAGAAAC, (Seq. ID No. 600), AGTATTCTAGAAA, (Seq. ID No. 601), AGTATTCTAGAA, (Seq. ID No. 602), AGTATTCTAGA, (Seq. ID No. 603), AGTATTCTAG, (Seq. ID No. 604), AGTATTCTA, AGTATTCT, AGTATTC, AGTATT, AGTAT, AGTA, AGT, AG, or A.

### Claim 26 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the last 2 to 4 nucleotides at the 5′ terminal end are LNA nucleotides and the last 2 to 4 nucleotides at the 3′ terminal end are LNA nucleotides and between the LNA nucleotides at the 5′ terminal end and the LNA nucleotides at the 3′ terminal end at least 6 consecutive nucleotides are present which are non-LNA nucleotides or which are DNA nucleotides.

### Claim 27 (depends on 25)

The antisense-oligonucleotide according to claim 25, wherein the last 2 to 4 nucleotides at the 5′ terminal end are LNA nucleotides and the last 2 to 4 nucleotides at the 3′ terminal end are LNA nucleotides and between the LNA nucleotides at the 5′ terminal end and the LNA nucleotides at the 3′ terminal end at least 6 consecutive nucleotides are present which are non-LNA nucleotides or which are DNA nucleotides.

### Claim 28 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the LNA nucleotides are linked to each other through a phosphorothioate group or a phosphorodithioate group or wherein all nucleotides are linked to each other through a phosphate group or a phosphorothioate group or a phosphorodithioate group.

### Claim 29 (depends on 25)

The antisense-oligonucleotide according to claim 25, wherein the LNA nucleotides are linked to each other through a phosphorothioate group or a phosphorodithioate group or wherein all nucleotides are linked to each other through a phosphate group or a phosphorothioate group or a phosphorodithioate group.

### Claim 30 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the LNA nucleotides are selected from the group consisting of:
wherein
IL′ represents —X″—P(═X′)(X−)—;
X′ represents ═O or ═S;
X represents —O−, —OH, —ORH, —NHRH, —N(RH)2, —OCH2CH2ORH, —OCH2CH2SRH, —BH3−, —RH, —SH, —SRH, or —S−;
X″ represents —O—, —NH—, —NRH—, —CH2—, or —S—;
Y is —O—, —NH—, —NRH—, —CH2— or —S—;
RC and RH are independently of each other selected from hydrogen and C1-4-alkyl; and
B represents a nucleobase selected from the group consisting of:
adenine, thymine, guanine, cytosine, uracil, 5-methylcytosine, 5-hydroxymethyl cytosine, N4-methylcytosine, xanthine, hypoxanthine, 7-deazaxanthine, 2-aminoadenine, 6-methyladenine, 6-methylguanine, 6-ethyladenine, 6-ethylguanine, 2-propyladenine, 2-propylguanine, 6-carboxyuracil, 5,6-dihydrouracil, 5-propynyl uracil, 5-propynyl cytosine, 6-aza uracil, 6-aza cytosine, 6-aza thymine, 5-uracil, 4-thiouracil, 8-fluoroadenine, 8-chloroadenine, 8-bromoadenine, 8-iodoadenine, 8-aminoadenine, 8-thioladenine, 8-thioalkyladenine, 8-hydroxyladenine, 8-fluoroguanine, 8-chloroguanine, 8-bromoguanine, 8-iodoguanine, 8-aminoguanine, 8-thiolguanine, 8-thioalkylguanine, 8-hydroxylguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-trifluoromethyluracil, 5-fluorocytosine, 5-bromocytosine, 5-chlorocytosine, 5-iodocytosine, 5-trifluoromethylcytosine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 7-deaza-8-azaadenine, 3-deazaguanine, 3-deazaadenine, 2-thiouracil, 2-thiothymine, and 2-thiocytosine.

### Claim 31 (depends on 25)

The antisense-oligonucleotide according to claim 25, wherein the LNA nucleotides are selected from the group consisting of:
wherein
IL′ represents —X″—P(═X′)(X−)—;
X′ represents ═O or ═S;
X represents —O−, —OH, —ORH, —NHRH, —N(RH)2, —OCH2CH2ORH, —OCH2CH2SRH, —BH3−, —RH, —SH, —SRH, or —S−;
X″ represents —O—, —NH—, —NRH—, —CH2—, or —S—;
Y is —O—, —NH—, —NRH—, —CH2— or —S—;
RC and RH are independently of each other selected from hydrogen and C1-4-alkyl; and
B represents a nucleobase selected from the group consisting of:
adenine, thymine, guanine, cytosine, uracil, 5-methylcytosine, 5-hydroxymethyl cytosine, N4-methylcytosine, xanthine, hypoxanthine, 7-deazaxanthine, 2-aminoadenine, 6-methyladenine, 6-methylguanine, 6-ethyladenine, 6-ethylguanine, 2-propyladenine, 2-propylguanine, 6-carboxyuracil, 5,6-dihydrouracil, 5-propynyl uracil, 5-propynyl cytosine, 6-aza uracil, 6-aza cytosine, 6-aza thymine, 5-uracil, 4-thiouracil, 8-fluoroadenine, 8-chloroadenine, 8-bromoadenine, 8-iodoadenine, 8-aminoadenine, 8-thioladenine, 8-thioalkyladenine, 8-hydroxyladenine, 8-fluoroguanine, 8-chloroguanine, 8-bromoguanine, 8-iodoguanine, 8-aminoguanine, 8-thiolguanine, 8-thioalkylguanine, 8-hydroxylguanine, 5-fluorouracil, 5-bromouracil, 5-chlorouracil, 5-iodouracil, 5-trifluoromethyluracil, 5-fluorocytosine, 5-bromocytosine, 5-chlorocytosine, 5-iodocytosine, 5-trifluoromethylcytosine, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine, 7-deazaadenine, 7-deaza-8-azaadenine, 3-deazaguanine, 3-deazaadenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine.

### Claim 32 (depends on 22)

The antisense-oligonucleotide according to claim 22 having one of the following gapmer structures selected from the group consisting of: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, and 4-11-3.

### Claim 33 (depends on 25)

The antisense-oligonucleotide according to claim 25 having one of the following gapmer structures selected from the group consisting of: 3-8-3, 4-8-2, 2-8-4, 3-8-4, 4-8-3, 4-8-4, 3-9-3, 4-9-2, 2-9-4, 4-9-3, 3-9-4, 4-9-4, 3-10-3, 2-10-4, 4-10-2, 3-10-4, 4-10-3, 4-10-4, 2-11-4, 4-11-2, 3-11-4, and 4-11-3.

### Claim 34 (depends on 22)

The antisense-oligonucleotide according to claim 22, wherein the antisense oligonucleotides bind with 100% complementarity to the mRNA encoding TGF-RII and do not bind to any other region in the human transcriptome.

### Claim 35 (depends on 25)

The antisense-oligonucleotide according to claim 25, wherein the antisense oligonucleotides bind with 100% complementarity to the mRNA encoding TGF-RII and do not bind to any other region in the human transcriptome.

### Claim 36 (depends on 22)

A method for promoting regeneration and functional reconnection of damaged nerve pathways and/or for treatment and compensation of age induced decreases in neuronal stem cell renewal comprising administering to a patient an antisense-oligonucleotide according to claim 22.

### Claim 37 (depends on 25)

A method for promoting regeneration and functional reconnection of damaged nerve pathways and/or for treatment and compensation of age induced decreases in neuronal stem cell renewal comprising administering to a patient an antisense-oligonucleotide according to claim 25.

### Claim 38 (depends on 22)

A method for prophylaxis and treatment of a disease selected from the group consisting of neurodegenerative diseases, neuroinflammatory disorders, traumatic or posttraumatic disorders, neurovascular disorders, hypoxic disorders, postinfectious central nervous system disorders, fibrotic diseases, hyperproliferative diseases, cancer, tumors, presbyakusis and presbyopia comprising administering to a patient an antisense-oligonucleotide according to claim 22.

### Claim 39 (depends on 25)

A method for prophylaxis and treatment of a disease selected from the group consisting of neurodegenerative diseases, neuroinflammatory disorders, traumatic or posttraumatic disorders, neurovascular disorders, hypoxic disorders, postinfectious central nervous system disorders, fibrotic diseases, hyperproliferative diseases, cancer, tumors, presbyakusis and presbyopia comprising administering to a patient an antisense-oligonucleotide according to claim 25.

### Claim 40 (depends on 38)

The method according to claim 38, wherein the neurodegenerative diseases and neuroinflammatory disorders are selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Creutzfeldt Jakob disease, new variant of Creutzfeldt Jakobs disease, Hallervorden Spatz disease, Huntington's disease, multisystem atrophy, dementia, frontotemporal dementia, motor neuron disorders, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar atrophies, schizophrenia, affective disorders, major depression, meningoencephalitis, bacterial meningoencephalitis, viral meningoencephalitis, CNS autoimmune disorders, multiple sclerosis, acute ischemic/hypoxic lesions, stroke, CNS and spinal cord trauma, head and spinal trauma, brain traumatic injuries, arteriosclerosis, atherosclerosis, microangiopathic dementia, Binswanger' disease, retinal degeneration, cochlear degeneration, macular degeneration, cochlear deafness, AIDS related dementia, retinitis pigmentosa, fragile X associated tremor/ataxia syndrome, progressive supranuclear palsy, striatonigral degeneration, olivopontocerebellear degeneration, Shy Drager syndrome, age dependant memory deficits, neurodevelopmental disorders associated with dementia, Down's Syndrome, synucleinopathies, superoxide dismutase mutations, trinucleotide repeat disorders, trauma, hypoxia, vascular diseases, vascular inflammations, and CNS ageing and wherein the fibrotic diseases are selected from the group consisting of: pulmonary fibrosis, cystic fibrosis, hepatic cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, and residuums after Lupus erythematodes.

### Claim 41 (depends on 39)

The method according to claim 39, wherein the neurodegenerative diseases and neuroinflammatory disorders are selected from the group consisting of: Alzheimer's disease, Parkinson's disease, Creutzfeldt Jakob disease, new variant of Creutzfeldt Jakobs disease, Hallervorden Spatz disease, Huntington's disease, multisystem atrophy, dementia, frontotemporal dementia, motor neuron disorders, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar atrophies, schizophrenia, affective disorders, major depression, meningoencephalitis, bacterial meningoencephalitis, viral meningoencephalitis, CNS autoimmune disorders, multiple sclerosis, acute ischemic/hypoxic lesions, stroke, CNS and spinal cord trauma, head and spinal trauma, brain traumatic injuries, arteriosclerosis, atherosclerosis, microangiopathic dementia, Binswanger' disease, retinal degeneration, cochlear degeneration, macular degeneration, cochlear deafness, AIDS related dementia, retinitis pigmentosa, fragile X associated tremor/ataxia syndrome, progressive supranuclear palsy, striatonigral degeneration, olivopontocerebellear degeneration, Shy Drager syndrome, age dependant memory deficits, neurodevelopmental disorders associated with dementia, Down's Syndrome, synucleinopathies, superoxide dismutase mutations, trinucleotide repeat disorders, trauma, hypoxia, vascular diseases, vascular inflammations, and CNS ageing and wherein the fibrotic diseases are selected from the group consisting of: pulmonary fibrosis, cystic fibrosis, hepatic cirrhosis, endomyocardial fibrosis, old myocardial infarction, atrial fibrosis, mediastinal fibrosis, myelofibrosis, retroperitoneal fibrosis, progressive massive fibrosis, nephrogenic systemic fibrosis, Crohn's Disease, keloid, systemic sclerosis, arthrofibrosis, Peyronie's disease, Dupuytren's contracture, and residuums after Lupus erythematodes.

### Claim 42 (depends on 22)

A pharmaceutical composition comprising at least one antisense-oligonucleotide according to claim 22 together with at least one pharmaceutically acceptable carrier, excipient, adjuvant, solvent or diluent.