IP Library Granted Patent US 12,292,451
Granted Patent B2
US 12,292,451 · App. 15/734,631 · Granted May 6, 2025

ApoA1 exchange rate assays in serum

Inventors: Jonathan D. Smith (Shaker Heights, OH); Stanley L. Hazen (Pepper Pike, OH); Shuhui Wang Lorkowski (Shaker Heights, OH)
Assignee: CLEVELAND CLINIC FOUNDATION
G01N33/92G16H15/00G16H50/30G01N2333/775
View Patent ↗
Loading inventors, assignments & file history…
Monitor This Case
Get email alerts when status or documents change.
Order Certified Copies
Most orders are placed with the USPTO same day — all within 24 business hours.
Order via The Patent Place →
Pre-filled with this patent's details
Quick Facts
Patent No.
US 12,292,451
App. No.
15/734,631
Granted
May 6, 2025
Kind
B2
Abstract

Provided herein are compositions, systems, kits, and methods for performing an apoA1 exchange assay to determine the risk of MACE and/or for conducting an action based on the assay results. In some embodiments, methods are provided for generating, or receiving, a report that graphically displays: i) the subjects ApoA1 exchange rate in a sample as lower than a control or threshold value, and ii) the subjects risk of a major adverse cardiac event (MACE) and/or cardiovascular disease as being higher than normal.

Claims (15)

1. A method of detecting lipid-free apoA1 reporter molecules in a serum sample from a human subject comprising:

a) contacting a serum sample from a human subject with lipid-free apoA1 reporter molecules,

wherein said serum sample comprises HDL molecules and LDL molecules,

wherein said lipid-free apoA1 reporter molecules each comprise at least a portion of human ApoA1 that is labeled with: i) nitrobenzoxadiazole, a lipid sensitive label whose fluorescence increases in a hydrophobic environment, and ii) a lipid insensitive fluorescent label; and

b) detecting: i) a first signal from said lipid sensitive label, and ii) a second signal from said lipid insensitive label, wherein said lipid-free apoA1 reporter molecules exchange into said HDL molecules in said serum sample at a rate detectable by said first and second signals together.

2. The method of claim 1 , further comprising: generating a report that graphically displays said subject's ApoA1 exchange rate.

3. The method of claim 2 , wherein said report graphically displays said subject's ApoA1 exchange rate as less than said a threshold value of 0.85.

4. The method of claim 3 , wherein said subject's ApoA1 exchange rate is presented in a column indicative of being lower than said threshold value.

5. The method of claim 3 , wherein said subject's ApoA1 exchange rate is presented in a color indicative of being lower than said threshold value.

6. The method of claim 2 , wherein said report graphically displays:

i) said subject's ApoA1 exchange rate in said sample as: i) lower than a control value, and/or ii) lower than a threshold value of 0.85; and

ii) said subject's risk of a major adverse cardiac event (MACE) and/or cardiovascular disease being higher than normal.

7. The method of claim 6 , wherein said subject's ApoA1 exchange rate is presented in a column indicative of being lower than said control value.

8. The method of claim 6 , wherein said subject's ApoA1 exchange rate is presented in a color indicative of being lower than said control value.

9. The method of claim 6 , wherein said control value is based on the average ApoA1 exchange rate from a plurality of healthy individuals or a plurality of individuals without cardiovascular disease.

Assignments (2)
CONFIRMATORY LICENSE Recorded Feb 6, 2023
From: CLEVELAND CLINIC FOUNDATION
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 062651/0711 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Mar 31, 2021
From: SMITH, JONATHAN D.; HAZEN, STANLEY L.; LORKOWSKI, SHUHUI W.
To: THE CLEVELAND CLINIC FOUNDATION
Reel/Frame 055785/0807 →
Continuity (2)
Provisional Application 62682628 · Dec 3, 2020
Related Publication 20210231691A1 · Jul 29, 2021
References Cited (40)
US 9494606B2 · Sacks · 2016 [cited by examiner]
US 20030100486A1 · Ridker et al. · 2003 [cited by applicant]
US 20090035874A1 · Hazen et al. · 2009 [cited by applicant]
US 20110070223A1 · Wolfert · 2011 [cited by examiner]
US 20110245340A1 · Medford · 2011 [cited by examiner]
US 20130108549A1 · Orser et al. · 2013 [cited by applicant]
US 20140243233A1 · Altmann · 2014 [cited by examiner]
US 20150301070A1 · Meikle et al. · 2015 [cited by applicant]
US 20150331000A1 · Collier · 2015 [cited by examiner]
US 20150376704A1 · Harrington · 2015 [cited by examiner]
US 20160024182A1 · Smith et al. · 2016 [cited by applicant]
US 20160274134A1 · Mutharasan · 2016 [cited by examiner]
US 20160305967A1 · Oda · 2016 [cited by applicant]
US 20170336425A1 · Smith et al. · 2017 [cited by applicant]
US 20180054152A1 · Leman · 2018 [cited by examiner]
US 20180074080A1 · Thaxton · 2018 [cited by examiner]
WO WO2010138899 · 2010 [cited by applicant]
Wang et al., Supplement of ABCA1 mediates unfolding of apoAl N-terminus on the cell surface prior to lipidation and release of nascent HDL, 2014, Arterioscler Thromb Vasc Biol., 33(6): supplement (Year: 2014). [cited by examiner]
Lund-Katz et al., Kinetics and Mechanism of Free Cholesterol Exchange between Human Serum High- and Low-Density Lipoproteins, 1982, Biochemistry, 21, p. 2964-2969. (Year: 1982). [cited by examiner]
International Search Report and Written Opinion for PCT/US2019/035228. Mailed Aug. 28, 2019. 12 pages. [cited by applicant]
Assmann et al., High-density lipoprotein cholesterol as a predictor of coronary heart disease risk. The PROCAM experience and pathophysiological implications for reverse cholesterol transport. Atherosclerosis. Jul. 1996… [cited by applicant]
Barter et al., Effects of torcetrapib in patients at high risk for coronary events. N Engl J Med. Nov. 22, 2007;357(21):2109-22. [cited by applicant]
Block et al., Effects of aspirin in combination with EPA and DHA on HDL-C cholesterol and ApoA1 exchange in individuals with type 2 diabetes mellitus. Prostaglandins Leukot Essent Fatty Acids. Nov. 2017;126:25-31. [cited by applicant]
Boden et al., Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy. N Engl J Med. Dec. 15, 2011;365(24):2255-67. [cited by applicant]
Borja et al., HDL-apoA-I exchange: rapid detection and association with atherosclerosis. PLoS One. Aug. 28, 2013;8(8):e71541. 11 pages. [cited by applicant]
Borja et al., HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity. J Lipid Res. Oct. 2015;56(10):2002-9. [cited by applicant]
Cavigiolio et al., Exchange of apolipoprotein A-I between lipid-associated and lipid-free states: a potential target for oxidative generation of dysfunctional high density lipoproteins. J Biol Chem. Jun. 11, 2010;285(24… [cited by applicant]
Gordon et al., High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. May 1977;62(5):707-14. [cited by applicant]
Handa et al., Kinetic and thermodynamic analyses of spontaneous exchange between high-density lipoprotein-bound and lipid-free apolipoprotein A-I. Biochemistry. Feb. 3, 2015;54(4):1123-31. [cited by applicant]
Heier et al., Reduced HDL function in children and young adults with type 1 diabetes. Cardiovasc Diabetol. Jul. 6, 2017;16(1):85. 8 pages. [cited by applicant]
Khera et al., Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med. Jan. 13, 2011;364(2):127-35. [cited by applicant]
Knapp et al., Clinical Epidemiology and Biostatistics. William and Wilkins, Harual Publishing Co. Malvern, Pa. 1992. TOC only. 7 pages. [cited by applicant]
Lincoff et al., Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease. N Engl J Med. May 18, 2017;376(20):1933-1942. [cited by applicant]
Neufeld et al., ApoA-I-Mediated Lipoprotein Remodeling Monitored with a Fluorescent Phospholipid. Biology (Basel). Jul. 12, 2019;8(3):53. 22 pages. [cited by applicant]
Rohatgi et al., HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. Dec. 18, 2014;371(25):2383-93. [cited by applicant]
Saleheen et al., Association of HDL cholesterol efflux capacity with incident coronary heart disease events: a prospective case-control study. Lancet Diabetes Endocrinol. Jul. 2015;3(7):507-13. [cited by applicant]
Sarzynski et al., Effects of Increasing Exercise Intensity and Dose on Multiple Measures of HDL (High-Density Lipoprotein) Function. Arterioscler Thromb Vasc Biol. Apr. 2018;38(4):943-952. [cited by applicant]
Schwartz et al., Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. Nov. 29, 2012;367(22):2089-99. [cited by applicant]
Voight et al., Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. Aug. 11, 2012;380(9841):572-80. [cited by applicant]
Wang et al., ABCA1 mediates unfolding of apolipoprotein AI N terminus on the cell surface before lipidation and release of nascent high-density lipoprotein. Arterioscler Thromb Vasc Biol. Jun. 2013;33(6):1197-205. [cited by applicant]