Resumen
Method for the diagnosis, prognosis and for predicting response to treatment with NOS2 inhibitor, sGC inhibitor and/or PRKG1 inhibitors based on the detection of nitrated proteins or cGMP. Composition comprising NOS2, soluble guanylate cyclase (sGC) and/or PRKG1 inhibitors for use in the therapy of thoracic aortic aneurysm and dissection (TAAD) in patients having high levels of nitrated proteins or cGMP. Composition comprising soluble guanylate cyclase (sGC) inhibitor and/or PRKG1 inhibitor for use in the therapy of thoracic aortic aneurysm and dissection.
Reivindicaciones
CLAIMS 1. In vitro method for the diagnosis and/or prognosis of thoracic aortic aneurysm which comprises measuring the circulating level of nitrated proteins and/or cGMP in a biological sample obtained from the patient, wherein the determination of higher level of nitrated proteins and/or cGMP as compared with a pre-established threshold level, is an indication that the patient is suffering from thoracic aortic aneurysm or has a bad prognosis. 2. In vitro method for predicting the response to a treatment with NOS2 and/or sGC inhibitors in patients suffering from thoracic aortic aneurysm which comprises measuring the circulating level of nitrated proteins and/or cGMP in a biological sample obtained from the patient, wherein the determination of lower level of nitrated proteins as compared with a pre-established threshold level, is an indication that the patients are responding to the treatment with NOS2 inhibitors, and wherein the determination of lower level of cGMP as compared with a pre-established threshold level, is an indication that the patients are responding to the treatment with NOS2 or sGC inhibitors. 3. In vitro method for selecting patients suffering from thoracic aortic aneurysm who may respond to a treatment with NOS2, sGC and/or PRKG1 inhibitors, which comprises measuring the circulating level of nitrated proteins and/or cGMP in a biological sample obtained from the patient, wherein the determination of higher level of nitrated proteins and/or cGMP as compared with a pre-established threshold level, is an indication that the patients may respond to the treatment with NOS2, sGC and/or PRKG1 inhibitors. 4. In vitro method for monitoring patients suffering from thoracic aortic aneurysm which comprises measuring the circulating level of nitrated proteins and/or cGMP in a biological sample obtained from the patients, wherein the determination of higher level of nitrated proteins and/or cGMP as compared with a pre-established threshold level, is an indication that the patients are suffering from thoracic aortic aneurysm, and wherein the determination of lower level of nitrated proteins and/or cGMP as compared with a pre-established threshold level, is an indication that the patients are not suffering from thoracic aortic aneurysm. 5. In vitro method, according to any of the claims 1 to 4, wherein the biological sample is plasma, blood or serum. 6. In vitro method, according to any of the claims 1 to 5, wherein the medical indication is bicuspid aortic valve; a syndromic thoracic aortic aneurysm (TAA) such as Marfan Syndrome, vascular Ehlers-Danlos Syndrome, Loeys-Dietz Syndrome (Types 1 and 2), and Familial thoracic aortic aneurysm and dissection (familial TAAD) or a non- syndromic TAA. 7. In vitro use of nitrated proteins and/or cGMP for the diagnosis or prognosis of thoracic aortic aneurysm, for predicting the response to a treatment with NOS2, sGC and/or PRKG1 inhibitors in patients suffering from thoracic aortic aneurysm, for selecting patients suffering from thoracic aortic aneurysm who may respond to a treatment with NOS2, sGC and/or PRKG1 inhibitors, or for monitoring patients suffering from thoracic aortic aneurysm. 8. Composition comprising NOS2, sGC and/or PRKG1 inhibitors for use in the treatment of patients suffering from thoracic aortic aneurysm who have higher circulating levels of nitrated proteins and/or cGMP as compared with a pre- established threshold level determined in control subjects. 9. Composition comprising NOS2, sGC and/or PRKG1 inhibitors for use in the treatment of patients suffering from thoracic aortic aneurysm, according to claim 8, which comprises: (i) determining in a biological sample obtained from the patient whether the circulating levels of nitrated proteins and/or cGMP are/is higher as compared with a pre-established level determined in control subjects and (ii) administering to the patient an effective amount of a composition comprising NOS2, sGC and/or PRKG1 inhibitors if it is determined that the circulating levels of nitrated proteins and/or cGMP are/is higher as compared with a pre-established threshold level determined in control subjects. 10. Composition comprising sGC and/or PRKG1 inhibitors for use in the treatment of thoracic aortic aneurysm. 11. Composition for use, according to claim 10, comprising sGC and/or PRKG1 in combination with NOS2 inhibitors. 12. Composition for use, according to any of the claims 8 to 11, wherein the patient is suffering from bicuspid aortic valve; a syndromic thoracic aortic aneurysm (TAA) such as Marfan Syndrome, vascular Ehlers Danlos, Loeys Dietz Syndrome (Types 1 and 2), and Familial thoracic aortic aneurysm and dissection (familial TAAD) or a non-syndromic TAA. 13. Composition for use, according to any of the claims 8 to 12, wherein the inhibitor is a pharmacological inhibitor or a molecule which induces gene silencing. 14. Composition for use, according to any of the claims 8 to 13, wherein the sGC inhibitor is ODQ, the PRKG1 inhibitor is KT5823, the NOS2 inhibitor is selected from the group comprising 1400W, L-NAME, GW274150, GW273629, Aminoguanidine (AG) hydrocloride, L-NIL and clotrimazole, and the molecule which induces gene silencing is a shRNA. 15. Composition for use, according to any of the claims 8 to 14, characterized in that it is a pharmaceutical composition which optionally comprises pharmaceutically acceptable excipients or carriers.
