Biomarker of polycystic kidney disease and uses thereof
Provided herein are methods for determining the efficacy of treatment for polycystic kidney disease (PKD) in a patient, diagnosing PKD in a patient, staging PKD in a patient, and monitoring PKD in a patient. These methods include determining a single or multiple levels of AMBP. Also provided are kits that include an antibody specifically binds to AMBP protein and at least one antibody that specifically binds to an additional marker of PKD.
1. A method of determining the efficacy of treatment for polycystic kidney disease (PKD) in a patient, the method comprising:
(a) providing a first sample comprising urine obtained from a PKD patient;
(b) determining a level of a-l-microglobulin/bikunin precursor (AMBP) protein in the first sample;
(c) administering a PKD treatment to the patient;
(d) providing a second sample comprising urine from the patient after step (c) and determining a level of AMBP protein in the second sample; and
(e) identifying the administered treatment as effective if the level in the second sample is lower than the level in the first sample.
2. The method of claim 1 , wherein the PKD patient has autosomal dominant PKD.
3. The method of claim 1 , wherein the PKD patient has autosomal recessive PKD.
4. The method of claim 1 , wherein the PKD treatment comprises a glucosyl ceramide synthase (GCS) inhibitor.
5. The method of claim 4 , wherein the GCS inhibitor is selected from the group consisting of:
(S)-quinuclidin-3-yl (2-(4′-(2-methoxyethoxy)-[1,1′-biphenyl]-4-yl)propan-2-yl)carbamate;
4-fluoro-1-(5-fluoro-4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3 0.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
quinuclidin-3-yl (2-(4′-fluoro-[1,1′-biphenyl]-3-yl)propan-2-yl)carbamate; and
carbamic acid, N41 42-(4-fluorophenyl)-4-thiazolyl]-1-methylethyl]-, (3 S)-1-azabicyclo[2.2.2]oct-3-yl ester.
6. The method of claim 4 , further comprising: (f) administering to the patient additional doses of GCS inhibitor if the treatment is identified as being effective.
7. The method of claim 6 , wherein the additional doses of GCS inhibitor comprise
(S)-quinuclidin-3-yl (2-(4′-(2-methoxyethoxy)-[1,1′-biphenyl]-4-yl)propan-2-yl)carbamate;
4-fluoro-1-(5-fluoro-4-(442-methoxy ethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3 0.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-((2-methoxyethoxy)methyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(methoxymethyl)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(3-methylquinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-methoxyethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(quinuclidin-3-yl)piperidine-4-carboxamide;
4-fluoro-1-(4-(4-(2-fluoroethoxy)phenyl)pyrimidin-2-yl)-N-(4-methyl-1-azabicyclo[3.2.2]nonan-4-yl)piperidine-4-carboxamide;
quinuclidin-3-yl (2-(4′-fluoro-[1,1′-biphenyl]-3-yl)propan-2-yl)carbamate; or
carbamic acid, N41 42-(4-fluorophenyl)-4-thiazolyl]-1-methylethyl]-, (3 S)-1-azabicyclo[2.2.2]oct-3-yl ester.
8. The method of claim 1 , wherein the PKD treatment comprises a CDK inhibitor.
9. The method of claim 8 , wherein the CDK inhibitor is R-roscovitine or S-CR8.
10. The method of claim 8 , further comprising: (f) administering to the patient additional doses of CDK inhibitor if the treatment is identified as being effective.
11. The method of claim 10 , wherein the additional doses of CDK inhibitor comprise R-roscovitine or S-CR8.
12. The method of claim 1 , wherein (b) and (d) comprise contacting the sample with an antibody that binds specifically to AMBP protein.