Treatment of aneurysms
View Patent ↗The present invention provides methods for detecting and/or treating a subject having an aneurysm or at risk for developing an aneurysm. It has been discovered that a key metabolite of the kynurenine (Kyn) pathway, a major route for the metabolism of essential amino acid tryptophan (Trp) into nicotinamide adenine dinucleotide (NAD+), plays a critical role in the formation of aneurysms, for example abdominal aortic aneurysms. In particular, it has been discovered that 3-Hydroxyanthranilic acid (3-HAA), a product of kynureninase (KYNU), plays a causative role in the formation of aneurysms by, for example exerting pro-inflammatory effects on vascular smooth muscle cells. It has further been discovered that elevated levels of 3-HAA are indicative of the presence and/or progression of an aneurysm, and 3-HAA levels correlate with the size (aortic diameter) of the aneurysm.
1. A method of treating a subject with an aneurysm comprising administering to the subject an effective amount of a KYNU inhibitor, a KMO inhibitor, a 3-HAO upregulator, or acipimox, wherein the aneurysm is an abdominal aortic aneurysm (AAA).
2. The method of claim 1 , wherein the inhibitor is a KYNU inhibitor.
3. The method of claim 2 , wherein the KYNU inhibitor is selected from 2-Amino-4-[3′-hydroxyphenyl]-4-hydroxybutanoic acid,
(4R)-dihydro-L-kynurenine, (4S)-dihydro-L-kynurenine,
benserazide, o-Methoxybenzoylalanine (OMBA), and (m-Nitrobenzoyl)alanine (NBA), or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 , wherein the inhibitor is a KMO inhibitor.
5. The method of claim 4 , wherein the KMO inhibitor is selected from GSK180, (R)-3-(5-chloro-6-(1-phenylethoxy)benzo[d]isoxazol-3-yl)propanoic acid, CHDI-340246, des-amino FCE 28833, UPF 648, and Ro-61-8048, or a pharmaceutically acceptable salt thereof.
6. The method of claim 1 , wherein the compound is acipimox, or a pharmaceutically acceptable salt thereof.
7. A method of reducing the risk of an aortic dissection in a subject having an underlying medical condition which predisposes the subject to the sudden dissection of an artery comprising administering to the subject an effective amount a KYNU inhibitor, a KMO inhibitor, a 3-HAO upregulator, or acipimox.
8. The method of claim 2 , wherein the subject has an underlying medical disorder selected from Marfan syndrome, Loeys-Dietz syndrome, aneurysms-osteoarthritis syndrome, Ehlers-Danlos syndrome, familial thoracic aortic aneurysm/dissection, Shprintzen-Goldberg syndrome, cutis laxa syndrome, aortic valve disease, arterial tortuosity syndrome, X-linked Alport syndrome, Turner syndrome, a congenital heart malformation, a mutation in the gene COL1A1, a mutation in the gene COL1A2, a mutation in the gene MED12, a mutation in the gene SMAD4, a mutation in the gen PLOD3, a mutation in the gene ENG, a mutation in the gene ACVRL1, and a mutation in the gene NF1.
9. The method of claim 7 , wherein the inhibitor is a KYNU inhibitor.
10. The method of claim 9 , wherein the KYNU inhibitor is selected from 2-Amino-4-[3′-hydroxyphenyl]-4-hydroxybutanoic acid,
(4R)-dihydro-L-kynurenine, (4S)-dihydro-L-kynurenine,
benserazide, o-Methoxybenzoylalanine (OMBA), and (m-Nitrobenzoyl)alanine (NBA), or a pharmaceutically acceptable salt thereof.
11. The method of claim 7 , wherein the inhibitor is a KMO inhibitor.
12. The method of claim 11 , wherein the KMO inhibitor is selected from GSK180, (R)-3-(5-chloro-6-(1-phenylethoxy)benzo[d]isoxazol-3-yl)propanoic acid, CHDI-340246, des-amino FCE 28833, UPF 648, and Ro-61-8048, or a pharmaceutically acceptable salt thereof.
13. The method of claim 7 , wherein the compound is acipimox, or a pharmaceutically acceptable salt thereof.
14. A method of treating an aneurysm in a subject comprising: i. determining the level of 3-HAA present in a sample from the subject; ii. comparing the subject's level of 3-HAA to a range of standardized levels of 3-HAA derived from individuals with an aneurysm (“aneurysmal range”); and, iii. performing a medical intervention on the subject if the subject's levels of 3-HAA falls within the aneurysmal range, wherein the medical intervention comprises administering to the subject an effective amount of a KYNU inhibitor, a KMO inhibitor, a 3-HAO upregulator, or acipimox, or a pharmaceutically acceptable salt thereof.
15. The method of claim 14 , wherein the aneurysmal range is an abdominal aortic aneurysmal range (“AAA aneurysmal range”).
16. The method of claim 14 , wherein the aneurysmal range is a thoracic aortic aneurysmal range (“TAA aneurysmal range”).
17. The method of claim 14 , wherein the aneurysmal range is a cerebral aneurysmal range (“CA aneurysmal range”).
18. The method of claim 14 , wherein the medical intervention comprises administering to the subject an effective amount of acipimox, or a pharmaceutically acceptable salt thereof.
19. A method of treating a subject with an aneurysm consisting of administering to the subject an effective amount of a KYNU inhibitor, a KMO inhibitor, a 3-HAO upregulator, or acipimox.