# US 2018/0023079 A1 · Circular RNA For The Diagnosis Of Cardiovascular And Inflammatory Diseases > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2018/0023079 A1 - Document ID: US20180023079A1 - Status: Published application - Kind: A1 - Application number: 15/548,325 - Filed: 2016-02-03 - Published: 2018-01-25 - Earliest claimed: 2015-02-03 - Assignees: Johann Wolfgang Goethe-Universität Frankfurt am Main - Applicants: Johann Wolfgang Goethe-Universität Frankfurt am Main - Inventors: Stefanie DIMMELER; Nicolas JAÉ; Niels BOECKEL; Andreas M. ZEIHER - Web page: https://patentgrep.com/patent/US20180023079A1 ## 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)} - A61K 31/713: Double-stranded nucleic acids or oligonucleotides - A61P 9/00: Drugs for disorders of the cardiovascular system - C12Q 1/6883: for diseases caused by alterations of genetic material - C12N 2310/10: Type of nucleic acid - C12N 2310/113: targeting other non-coding nucleic acids, e.g. antagomirs - C12N 2310/14: interfering nucleic acids [NA] - C12N 2310/20: involving clustered regularly interspaced short palindromic repeats [CRISPR] - C12N 2310/532: Closed or circular - 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) - 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 - 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 The present invention associates multiple circular (circRNA) with key functions of endothelial cells. The present invention provides circRNA transcripts that are correlated with cardiovascular diseases, in particular acute myocardial infarction. The circRNA of the invention therefore serve as biomarkers in the diagnosis of cardiovascular disorders. The invention provides the new nucleic acid molecules as well as diagnostic kits and compositions comprising the nucleic acids. Modulation of the expression of the circRNA of the invention further leads to endothelial cell sprouting, and therefore is applied as a treatment for cardiovascular diseases or pathological angiogenesis. The invention provides therapeutic agents modulating circRNA expression or function. Further aspects of the invention provide novel circRNA for the treatment of inflammatory diseases. ## Claims ### Claim 1 A nucleic acid, comprising a) A sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, b) A sequence which is complementary to or binds to a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, c) A sequence of at least 5 to 50 successive nucleic acid residues of a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, and/or d) A sequence which is complementary to or binds to a sequence of at least 5 to 50 successive nucleic acid residues of a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16. ### Claim 2 (depends on 1) The nucleic acid according to claim 1, which is a DNA or RNA, and which is single stranded or double stranded, and which is circular or linear. ### Claim 3 An in-vitro or ex-vivo method of predicting, monitoring and/or diagnosing a cardiovascular disease in a subject, comprising the steps of: a) Providing a biological sample from the subject, b) Determining the level of one or more non-coding circular RNA transcripts (circRNA) in the biological sample, wherein the circRNA transcript is selected from a circRNA comprising a sequence shown in any of SEQ ID NO: 1 to 16; c) Comparing the level of the circRNA in the biological sample to a control level of the one or more circRNA transcripts; d) Predicting, monitoring and/or diagnosing the subject as having the cardiovascular disease when the level of the one or more circRNA in the biological sample is higher or lower compared to the control level. ### Claim 4 (depends on 3) The method according to claim 3, wherein the cardiovascular disease is selected from atherosclerosis, a coronary heart disease, an acute coronary symptom, preferably unstable angina pectoris or acute myocardial infarction (AMI), stable angina pectoris, stroke, preferably ischemic stroke, inflammation or autoimmune disease associated artheriosclerosis or restenosis. ### Claim 5 (canceled) ### Claim 6 (depends on 3) The method according to claim 3, wherein the biological sample is a venous or aortic plasma sample. ### Claim 7 (depends on 3) The method according to claim 3, wherein a higher level of a circRNA comprising the sequence shown in SEQ ID NO: 2 in a sample of venous plasma of the subject compared to the control level indicates acute myocardial infarction; and/or wherein a higher level of a circRNA comprising the sequence shown in SEQ ID NO: 1 and/or SEQ ID NO: 4 in a sample of aortic plasma of the subject compared to the control level indicates acute myocardial infarction. ### Claim 8 A compound for use in the treatment of a proliferative disease or a disease associated with endothelial cell dysfunction, wherein the compound is an agonist of or is an antagonist of, a non-coding circular RNA (circRNA) comprising a sequence shown in any of SEQ ID NO: 1 to 16. ### Claim 9 (depends on 8) The compound for use according to claim 8, wherein the disease associated with endothelial cell dysfunction is pathological angiogenesis and wherein the compound is a) An agonist of a circRNA comprising a sequence shown in SEQ ID NO: 2 and/or 9, or b) An antagonist of a circRNA comprising a sequence shown in SEQ ID NO: 4 and/or 14; Or wherein the disease associated with endothelial cell dysfunction is a cardiovascular disease and wherein the compound is c) An antagonist of a circRNA comprising a sequence shown in SEQ ID NO: 2 and/or 9, or d). An agonist of a circRNA comprising a sequence shown in SEQ ID NO: 4 and/or 14; Or wherein the proliferative disease is a tumor disease, and wherein the compound is an antagonist of a circRNA shown in SEQ ID NO: 4. ### Claim 10 A compound for use in the treatment of a disease associated with inflammation, wherein the compound is an agonist of or is an antagonist of, a non-coding circular RNA (circRNA) comprising a sequence shown in [SEQ ID NO: 1 to 16]. ### Claim 11 (depends on 10) The compound for use according to claim 10, wherein the treatment of a pathological increased inflammation comprises the administration of an agonist of the circRNA cTRIO (SEQ ID NO: 14), and wherein the treatment of a pathological decreased inflammation comprises the administration of an antagonist of the circRNA cTRIO (SEQ ID NO: 14). ### Claim 12 (depends on 10) The compound for use according to claim 10, wherein a pathological increased inflammation is characterized by an elevated expression I-Cam and/or E-Selektin. ### Claim 13 (depends on 10) The compound for use according to claim 10, wherein the disease associated with inflammation is selected from inflammatory bowel disease, rheumatoid arthritis, urticuria, atherosclerotic vascular disease, psoriatic colitis, ulcerative colitis, acute eosinophilic pneumonia, severe asthma, idiopathic pulmonary fibrosis, liver fibrotic diseases, atopic dermatitis, systemic sclerosis, and autoimmune diseases. ### Claim 14 (depends on 10) The compound according to claim 10, wherein the circRNA agonist is selected from a nucleic acid comprising: a) A sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, b) A sequence which is complementary to or binds to a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, c) A sequence of at least 5 to 50 successive nucleic acid residues of a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16, and/or d) A sequence which is complementary to or binds to a sequence of at least 5 to 50 successive nucleic acid residues of a sequence having at least 70% sequence identity to a circular RNA comprising a sequence shown in any of SEQ ID NO: 1 to 16. ### Claim 15 (depends on 10) The compound according to claim 10, wherein an antagonist of a circRNA is selected from an inhibitory nucleic acid, such as an antisense construct, for example an siRNA, dsRNA, LNA, GapmeR, or a molecule that represses the expression and/or function of a circRNA, preferably wherein the antagonist is an antisense construct comprising a sequence that is complementary to a circRNA sequence of a circRNA comprising a sequence shown in any of SEQ ID NO 1 to 16, or is complimentary to a sequence having at least 70% sequence identity to a circRNA sequence of a circRNA comprising a sequence shown in any of SEQ ID NO: 1 to 16. ### Claim 16 An in-vitro or ex-vivo method for modulating endothelial cell function comprising contacting an endothelial cell with an agonist or antagonist of a circRNA, wherein the circRNA comprises a sequence shown in any of SEQ ID NO: 1 to 16. ### Claim 17 An in-vitro or ex-vivo method for the generation of vascular tissue material, the method comprising the steps of contacting an endothelial cell with an antagonist of a circRNA comprising a sequence shown in SEQ ID NO: 2 and/or 9, or an agonist of a circRNA comprising a sequence shown in SEQ ID NO: 4 and/or 14, preferably wherein the vascular tissue material is a blood vessel. ### Claim 18 (depends on 1) A pharmaceutical composition, comprising an agonist or antagonist of a circRNA comprising a sequence shown in any of SEQ ID NO: 1 to 27, preferably the pharmaceutical composition comprising an isolated nucleic acid according to claim 1, and optionally further comprising a pharmaceutically acceptable carrier and/or excipient. ### Claim 19 A method of in-vitro or ex-vivo modulation of endothelial cell function, comprising the step of contacting an endothelial cell with an agonist or antagonist of a circRNA comprising a sequence shown in any of SEQ ID NO: 1 to 16.