# US 10,871,495 B2 · Biomarkers of polycystic kidney disease and uses thereof

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- Number: US 10,871,495 B2
- Document ID: US10871495B2
- Status: Granted
- Kind: B2
- Application number: 15/501,496
- Filed: 2015-08-03
- Published: 2017-08-10
- Granted: 2020-12-22
- Earliest claimed: 2014-08-04
- Assignees: Genzyme Corporation
- Applicants: Genzyme Corporation
- Inventors: Oxana Beskrovnaya; Nikolai Bukanov; Sarah Moreno
- Web page: https://patentgrep.com/patent/US10871495B2

## CPC

- G01N 33/6893: {related to diseases not provided for elsewhere}
- A61P 13/12: of the kidneys
- G01N 33/492: {Determining multiple analytes}
- G01N 2800/347: Renal failures; Glomerular diseases; Tubulointerstitial diseases, e.g. nephritic syndrome, glomerulonephritis; Renovascular diseases, e.g. renal artery occlusion, nephropathy
- G01N 2800/52: Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
- G01N 2800/56: Staging of a disease; Further complications associated with the disease
- G01N 2800/60: Complex ways of combining multiple protein biomarkers for diagnosis
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

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 one or more markers selected from the group of Proliferating Cell Nuclear Antigen (PCNA), cyclin D1, cyclin D3, MAPKERK kinase 1 (MEK), ribosomal protein S6 (S6), phosphorylated ribosomal protein S6 (pS6), extracellular signal-regulated kinase (ERK), phosphorylated extracellular signal-regulated kinase (pERK), protein kinase B (Akt), phosphorylated protein kinase B (pAkt), caspase-2, total S6, and retinoblastoma binding protein (RBBP). Also provided are kits that include at least three antibodies that specifically bind to one or more of these markers.

## Claims

### Claim 1

A method of determining the efficacy of treatment for polycystic kidney disease (PKD) in a PKD patient, the method comprising:
(a) providing a first sample comprising urine obtained from the PKD patient at a first time point;
(b) concentrating the first sample for exosomes;
(c) determining the level(s) of at least one marker selected from the group consisting of Proliferating Cell Nuclear Antigen (PCNA), cyclin D1, cyclin D3, MAPK-ERK kinase 1 (MEK), and ribosomal protein S6 (S6) in the first sample after step (b);
(d) administering a glucosyl ceramide synthase (GCS) inhibitor to the PKD patient;
(e) providing a second sample comprising urine obtained from the PKD patient at a second time point after step (d) and performing steps (b) and (c) on the second sample; and
(f) identifying the administered treatment as being effective if the level of the at least one marker is decreased at the second time point as compared to the first time point.

### Claim 2 (depends on 1)

The method of claim 1, 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[3.2.2]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; and
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.

### Claim 3 (depends on 1)

The method of claim 1, wherein steps (c) and (e) comprise determining the levels of at least two markers selected from the group consisting of PCNA, cyclin D1, cyclin D3, MEK, and S6, and the administered GCS inhibitor is identified as being effective if at least one of the two levels is decreased at the second time point as compared to the first time point.

### Claim 4 (depends on 3)

The method of claim 3, wherein the administered GCS inhibitor is identified being effective if both levels are decreased at the second time point as compared to the first time point.