Vitamin E and derivatives thereof prevent potassium ion...

Details Vitamin E and derivatives thereof prevent potassium ion... Vitamin E and derivatives thereof prevent potassium ion...

1999-10-15

2003-04-01

Weber, Jon P. (Department: 1651)

Chemistry: molecular biology and microbiology

Treatment of micro-organisms or enzymes with electrical or...

Cell membrane or cell surface is target

C435S002000

Reexamination Certificate

active

06541229

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention concerns an improved process for rendering a cell-containing composition substantially free of enveloped and non-enveloped viruses contained therein without substantial disruption or inactivation of cells contained therein and without significant loss of labile proteins or other valuable biological components also contained therein.
2. Description of the Related Art
Viral inactivation of cell-containing composition by treatment with irradiation, e.g., UV or visible light, a photosensitizer compound and, optionally, one or more quencher compounds has been described in the applications and patents mentioned above, the entire disclosures of which are hereby incorporated by reference. Such treatments are known to cause K
+
leakage from red cells. See, e.g., J. van Steveninck et al., 1985, “The influence of cupric ions on porphyrin-induced photodynamic membrane damage in human red blood cells”,
Biochim. Biophys. Acta.,
821: 1-7.
Irradiation is used in other contexts involving cell-containing compositions for example, ionizing radiation, e.g., &ggr;-irradiation or X-irradiation, to prevent graft-versus host disease in immunodeficient patients. For this particular purpose, collected red cells increasingly are being stored for variable periods in transfusion service inventories following irradiation. Other reports of elevated K
+
in irradiated, stored RBC, have recently surfaced. See, for example, Elaine K. Jeter et al., 1991, “Effects of irradiation on red cells stored in CPDA-1 and CPD-ADSOL (AS-1)”,
Ann. Clin. Lab. Sci.,
21: 177-186; and A. M. Ramirez et al., 1987, “High potassium levels in stored irradiated blood”,
Transfusion,
27: 444-445. For blood centers offering red cell irradiation, prolonged storage following irradiation may expose selected patient populations to a significant K
+
load following transfusion.
It also is known that morphological deformations of erythrocytes are induced by hematoporphyrin- a photosensitizer compound- and light. See, for example, Bruria Lev et al., 1993, “Morphological Deformations of Erythrocytes Induced by Hematoporphyrin and Light”,
Lasers in the Life Sciences,
5: 219-230. Specifically, hematoporphyrin-bound cells displayed a marked reduction in membranal negative-charges and sialic acid residues on their cell membranes.
SUMMARY OF THE INVENTION
We have found that photodynamic treatment of cell-containing compositions, particularly, red cells, for virus sterilization causes K
+
leakage during storage prior to transfusion and loss of negative charges from the cell membrane. We have also found that these effects following photodynamic treatment for viral inactivation are even more pronounced than that observed following ionizing irradiation for the purposes of preventing graft-versus-host disease.
The leakage of K
+
from cells, e.g., red cells, may limit their usefulness, e.g., in transfusions. Moreover, loss of negative charges from the cell membrane reduces the life span of the cell, i.e., the life-time in the circulation in the case of a red cell.
Accordingly, it was the main object of the present invention to provide a means by which cell-containing compositions could be irradiated for the purpose of viral sterilization without inducing pronounced leakage of K
+
from cells or loss of negative charges from the cell membrane.
It was also an object of the present invention to provide a virus sterilization protocol more compatible for transfusion purposes.
It was another object of the present invention to provide a means by which a reduction could be effected in both K
+
leakage and the loss of cell membrane surface negative charges.
It was a further object of the present invention to provide a protocol for irradiation of blood in connection with the prevention of graft-versus-host disease by which processed blood more compatible for transfusion could be obtained.
These and other objects are met with the present invention which provides for a process for inactivating virus contained in a cell-containing composition without damaging desirable biological proteins contained in said cell-containing composition, said process comprising subjecting said cell-containing composition to a photosensitizer compound, light and a vitamin, e.g., vitamin E, or a derivative thereof, e.g., a derivative of vitamin E, for a period of time sufficient to substantially inactivate virus contained in said cell-containing composition.
We have discovered that vitamin E and its derivatives have the surprising ability to materially reduce leakage of K
+
from cells or loss of negative charges from the cell membrane.
The invention also relates to a process for preventing graft-versus-host disease comprising ionizing irradiation of red cells, wherein the improvement comprises incubating said red cells with vitamin E or a derivative thereof before, during and after said ionizing irradiation.
The invention further relates to a process for inactivating virus in a cell-containing composition by treating the cell-containing composition with a photodynamic compound under light, wherein the improvement comprises said treatment is carried out in the presence of vitamin E or a derivative thereof.


REFERENCES:
patent: 4847071 (1989-07-01), Bissett et al.
Chiu et al., “Peroxidation, Vitamin E, and Sickle-Cell Anemia”, Annals Of The New York Academy Of Sciences, (1982) vol. 393, 323-335.*
Wolters et al., “Membrane Radiosensitivity Of Fatty-Acid Supplemented Fibroblasts As Assayed By The Loss Of Intracellular Potassium”, Int J Radiat Biol Relat Stud Phys Chem Med, (1985) 48 (6), 963-974.

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