JP-7855210-B2 - Method for preserving and administering pre-β high-density lipoprotein extracted from human plasma.

Inventors

• ホリス ブライアン ブルーアー ジュニア
• マイケル エム マタン

Assignees

• エイチディーエル セラピューティクス インコーポレイテッド

Dates

Publication Date

20260508

Application Date

20181219

Priority Date

20171228

Claims (7)

1. A method for preserving pre-β high-density lipoprotein, including the following steps: A step of obtaining a batch of defatted plasma containing the aforementioned pre-β high-density lipoprotein; A step of testing a portion of a batch of degreased plasma to characterize the pre-β high-density lipoprotein, thereby determining at least partially a first characteristic of the pre-β high-density lipoprotein, wherein the first characteristic includes a first concentration of the pre-β high-density lipoprotein in the degreased plasma; A step of preserving a batch of degreased plasma by freezing the degreased plasma; A step of preparing the stored defatted plasma after a certain period of time, wherein the certain period of time is in the range of one week to three years; and A step of testing the prepared defatted plasma, comprising: determining a second characteristic of the pre-β high-density lipoprotein from the prepared preserved defatted plasma using 2D gel electrophoresis, wherein the second characteristic includes a second concentration of the pre-β high-density lipoprotein in the prepared preserved defatted plasma; comparing the second characteristic of the pre-β high-density lipoprotein with the first characteristic of the pre-β high-density lipoprotein to determine the degree of degradation; and determining whether the prepared preserved defatted plasma is suitable for administration based on the second characteristic of the pre-β high-density lipoprotein, wherein if 80% or less of the pre-β high-density lipoprotein is degraded into Apo A1, the prepared preserved defatted plasma is deemed suitable for administration .
2. The method according to claim 1, further comprising changing the amount of pre-β high-density lipoprotein before the preservation step to ensure that the concentration of pre-β high-density lipoprotein is in the range of 1 mg/dl to 400 mg/dl.
3. The method according to claim 1, wherein the preservation step includes freezing the batch at a temperature below -30°C.
4. The method according to claim 1, wherein the preparation step includes thawing the stored defatted plasma in a temperature range of 2°C to 26°C.
5. The method according to claim 1, wherein the preservation step includes exposing a volume of 1 milliliter to 2 liters of degreased plasma to a temperature below -30°C for less than 20 minutes.
6. The method according to claim 1, further comprising adding a preservative to the degreased plasma before storage.
7. The method according to claim 1, wherein the preparation step further comprises thawing the stored defatted plasma, and storing the thawed defatted plasma at a temperature in the range of 1°C to 6°C for 5 days or less.

Description

Cross-reference of related applications This application relies on U.S. Provisional Patent Application No. 62/611,098, filed on 28 December 2017, entitled “Method for the Treatment of Cholesterol-Related Diseases,” which is incorporated herein by reference in its entirety. This invention generally relates to systems, apparatus, and methods for removing lipids from HDL particles while substantially damaging LDL particles by in vitro treatment of plasma using one or more solvents, for the treatment of chronic cardiovascular disease and acute kidney disease. More specifically, this invention relates to systems and methods for preserving and administering pre-βHDL derived from non-autologous delipidated plasma. Familial hypercholesterolemia (FH) is a hereditary autosomal dominant disorder characterized by marked increases in low-density lipoprotein (LDL), tendon xanthomas, and juvenile coronary heart disease, resulting from mutations in the "FH gene," which contains the LDL receptor (LDLR), apolipoprotein B-100 (ApoB), or proprotein convertase subtilisin/kesin 9 type (PCSK9). FH presents a clinically recognizable phenotype consisting of severe hypercholesterolemia due to plasma LDL accumulation, cholesterol deposition in tendons and skin, and high-risk atherosclerosis, almost without exception manifesting as coronary artery disease (CAD). In FH patients, this gene mutation prevents the liver from effectively metabolizing (or removing) excess plasma LDL, leading to elevated LDL levels. When an individual inherits the defective FH gene from one parent, the form of FH is called heterozygous FH. Heterozygous FH is inherited in an autochromatic dominant manner and is a common genetic disorder, occurring in approximately 1 in 500 people in most countries. When an individual inherits the defective FH gene from both parents, the form of FH is called homozygous FH. Homozygous FH is extremely rare, occurring in approximately 1 in 160,000 to 1,000,000 people worldwide, and is characterized by LDL levels exceeding 700 mg/dl, more than 10 times the ideal level of 70 mg/dl desired for CVD patients. Due to high LDL levels, patients with homozygous FH develop malignant atherosclerosis (narrowing and occlusion of blood vessels) and early heart attacks. This process begins before birth and progresses rapidly. It can affect the coronary arteries, carotid arteries, aorta, and aortic valve. Heterozygous cholesterolemia (HeFH) is typically treated with statins, bile acid chelators, or other lipid-lowering drugs that reduce cholesterol levels, and/or by providing genetic counseling. Homozygous cholesterolemia (HoFH) often does not respond well to drug therapy and requires other treatments, including LDL apheresis (removal of LDL in a manner similar to dialysis), jejunal bypass surgery that dramatically lowers LDL levels, and, in some cases, liver transplantation. In recent years, some medications have been approved for HoFH patients. However, these medications only lower LDL and, while they may contribute somewhat to slowing the further progression of atherosclerosis, they do not stop its progression. Furthermore, these medications are known to have serious side effects. Cholesterol is either synthesized in the liver or obtained from the diet. LDL is involved in the transport of cholesterol from the liver to tissues in various parts of the body. However, when LDL accumulates in the artery walls, it is oxidized by oxygen free radicals released from chemical reactions in the body, and interacts harmfully with blood vessels. Modified LDL causes white blood cells to aggregate in the artery walls in the immune system, forming fatty substances called plaque and damaging the cell layer that reinforces blood vessels. Oxidized LDL also reduces the level of nitric oxide, which allows blood to flow freely by relaxing blood vessels. If this process continues, the artery walls slowly constrict, leading to arteriosclerosis and, consequently, reduced blood flow. As plaque gradually accumulates, coronary arteries can become blocked, potentially leading to a heart attack. Plaque accumulation can also occur in peripheral blood vessels, such as those in the legs; this condition is known as peripheral artery disease. Obstructions can also occur in the blood vessels supplying blood to the brain, potentially leading to ischemic stroke. The underlying symptom of this type of obstruction is the development of fatty deposits lining the vessel walls. In the United States, it is known that at least 2.7% of men and women aged 18 and older have a history of stroke. The prevalence of stroke is also known to increase with age. With the growing elderly population, the prevalence of stroke survivors is projected to increase, particularly among older women. A significant proportion of all strokes (at least 87%) are ischemic in nature. Furthermore, hypercholesterolemia and inflammation have been shown to be two major mechanisms involved in the development of atheroscl