KR-20260066367-A - Biomarker composition for diagnosis of arteriovenous malformation

Abstract

The present invention relates to a biomarker composition for diagnosing arteriovenous malformations. By comparing the expression levels of miRNAs in vascular endothelial cells derived from normal or arteriovenous malformation tissues, it was confirmed that the expression levels of five miRNAs—miR-135b-5p, miR-496, miR-132-3p, miR-193a-3p, and miR-193b-5p—significantly increased in vascular endothelial cells derived from arteriovenous malformation tissues, and the expression levels of two miRNAs—miR-137 and miR-30a-3p—significantly decreased in vascular endothelial cells derived from arteriovenous malformation tissues, thereby providing a novel biomarker capable of diagnosing arteriovenous malformations.

Inventors

• 정호윤
• 오은정
• 김현미
• 곽수인
• 허근
• 김경화

Assignees

• 경북대학교 산학협력단

Dates

Publication Date

20260512

Application Date

20241104

Claims (12)

1. Biomarker composition for diagnosing arteriovenous malformations comprising miRNAs miR-135b-5p and miR-137.
2. A biomarker composition according to claim 1, characterized in that the composition further comprises one or more miRNAs selected from miR-496, miR-132-3p, miR-193a-3p, miR-193b-5p, and miR-30a-3p.
3. A biomarker composition according to claim 1, characterized in that the miRNA is a vascular endothelial cell-derived miRNA.
4. A composition for diagnosing arteriovenous malformations comprising a preparation for measuring the expression level of the biomarker compositions of claims 1 to 3.
5. A diagnostic composition according to claim 4, wherein the above preparation is an oligopeptide, monoclonal antibody, polyclonal antibody, chimeric antibody, ligand, PNA (peptide nucleic acid), aptamer, antisense oligonucleotide, primer, or probe that specifically binds to miRNA, which is a biomarker.
6. A diagnostic kit for arteriovenous malformations comprising the diagnostic composition of claim 4.
7. A step of measuring the expression of miRNAs miR-135b-5p and miR-137 in biological samples isolated from subjects; and A method for providing information for the diagnosis of arteriovenous malformations, comprising the step of comparing the expression of the above miRNA with the miRNA expression level of a normal control group.
8. A method for providing information according to claim 7, characterized in that if the expression level of miR-135b-5p increases compared to a normal control group or the expression level of miR-137 decreases compared to a normal control group, the subject is judged to have a possibility of having an arteriovenous malformation.
9. A method for providing information according to claim 7, characterized in that, in the step of measuring the expression of the miRNA, the expression of one or more miRNAs selected from miR-496, miR-132-3p, miR-193a-3p, miR-193b-5p, and miR-30a-3p is further measured in the biological sample.
10. A method for providing information according to claim 9, characterized in that if the expression level of one or more selected miRNAs among miR-496, miR-132-3p, miR-193a-3p, and miR-193b-5 increases compared to a normal control group, or if the expression level of miR-30a-3p decreases compared to a normal control group, the subject is determined to have a possible arteriovenous malformation.
11. A method for providing information according to claim 7, characterized in that the biological sample is one or more selected from the group consisting of a patient's blood, plasma, serum, urine, and saliva.
12. A method for providing information according to claim 7, wherein the measurement is any one selected from the group consisting of reverse transcriptase polymerase chain reaction (RT-PCR), competitive reverse transcriptase polymerase chain reaction (competitive RT-PCR), real-time polymerase chain reaction (real-time RT-PCR), real-time quantitative RT-PCR, RNase protection method, Northern blotting, and gene chip.

Description

Biomarker composition for diagnosis of arteriovenous malformation The present invention relates to a biomarker composition for diagnosing arteriovenous malformations. Each type of vascular abnormality exhibits various surface characteristics, appearing flat or raised, and displays various colors such as blue, pink, purple, or red. Vascular anomalies are broadly classified into vascular tumors and malformations based on clinical features and medical history, and vascular malformations result from errors in the process of vascular development. Vascular malformations are classified into capillary malformations, venous malformations, arteriovenous malformations, and lymphatic malformations, each distinguished by consistent blood vessels exhibiting distinct characteristics. Among these, arteriovenous malformations (AVMs) are abnormal vascular malformations in which arteries and veins are directly connected without passing through capillaries, and they are the vascular malformation with the second worst prognosis after shunts. Arteriovenous malformations (AVMs) occur because the nutrient-supplying artery and the draining vein are directly connected, resulting in a high blood flow rate and the absence of an intermediate capillary network. AVMs can occur anywhere in the body and may be small and asymptomatic, but over time, they can progress into severe, life-threatening disorders. The pathophysiology is closely related to angiogenesis, which involves the direct shunting of high-pressure arterial blood into low-pressure veins to induce vasodilation and the recruitment of new blood vessels. This sustained stimulation causes high-flow circulation, creating a relatively hypoxic state in the surrounding tissues near the AVM. Vascular endothelium is a multifunctional organelle that undergoes adaptations to maintain homeostasis. Under physiological conditions, endothelial cells (ECs) play a crucial role in metabolic activation through paracrine, endocrine, and autocrine functions, alongside vascular homeostasis. All processes involving ECs require the precise synchronization of molecular and cellular events triggered by stimulating and inhibitory signals, ultimately leading to physiological regulation. Consequently, highly dynamic and dose-sensitive signaling complexes become key candidates for microRNAs (miRNAs) for the post-transcriptional mediated regulation of gene expression. Similarly, in numerous situations, vascular ECs are involved in regulating molecular and cellular processes regarding permeability, leukocyte adhesion, proliferation, and thrombosis. Furthermore, vascular endothelium undergoes vascular remodeling that can be influenced by vascular endothelial growth factor (VEGF) levels. VEGF is a factor that effectively induces angiogenesis and was initially characterized as a key growth factor for vascular ECs. This upregulation is observed in numerous tumors, and its role in promoting tumor angiogenesis has been clearly established. Since VEGF is an important regulator of vascular function and can potentially influence the development of AVM, its therapeutic effects are attracting attention. Tissue oxygenation depends on the balance between the oxygen supply delivered by blood vessels and the metabolic demands of the tissues. Hypoxia occurs secondarily due to insufficient oxygen supply resulting from extensive irregularities within the vascular system, including reduced and heterogeneous vascular density, dilated and tortuous vessels, atypical diameters, and vessel wall abnormalities. These morphological abnormalities collectively increase geometric resistance to blood circulation and impair vascular function. Low oxygen levels and their consequences play a significant role in the development of a wide range of human diseases, particularly those involving vascular structure. Since the vascular veins (AVMs) are exposed to relatively hypoxic conditions due to rapid shunting, they are believed to particularly affect pathophysiological processes where tissue oxygenation is insufficient. Meanwhile, miRNA, a type of ribonucleic acid (RNA) approximately 17–25 nucleotides in length, plays an important role in regulating gene expression. Although miRNA does not store genetic information, it functions as a powerful gene regulator by binding complementarily to various target messenger RNAs (mRNAs) to regulate gene transcription and translation. Most miRNAs are transcribed from DNA base sequences into primary miRNAs, processed into precursor miRNAs, and finally converted into mature miRNAs. Recent studies have reported the discovery of relevant miRNAs in patients with various diseases, including cancer, and have demonstrated that their expression levels are closely correlated with disease progression. However, knowledge regarding miRNAs involved in AVM, including their clinical significance, is currently limited. Figure 1 shows the results of analyzing the difference in miRNA expression between the normal group and the