Insulin-secreting cell lines, methods of production and use

Details Insulin-secreting cell lines, methods of production and use Insulin-secreting cell lines, methods of production and use

1996-06-04

1999-05-11

Ketter, James

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

424424, 435 11, 435 694, 4353201, 435353, 435 44, 435385, 435398, 4352841, 514 44, 530303, 536 2351, A61K35/55

Patent

active

059025778

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to the field of biology and, in particular, to the field of cell biology.
Its subject is in particular a novel cell line, capable of being implanted in a human organ so as to cause it to express the biological product which the novel cell line normally expresses in cultures.
The subject of the invention is specifically a novel glucose-sensitive cell line designated .beta. cell line (INS-I) whose principal property is the sensitivity to glucose. These cells are therefore characterized by a high content of insulin, the possibility of expressing glucokinase and the glucose carrier Glut 2 at levels comparable with those of normal .beta. cells and, in addition, these cells are made non-proliferating by genetic engineering.
This cell line is therefore capable of being transplanted into the organs of insulin-dependent subjects and of providing a "physiological" control of glycaemia in the case of insulin-dependent diabetes.
Organ transplant or tissue transplant forms part of the therapeutic tools used in a number of diseases. More recently, genetic engineering techniques have led to other possibilities being envisaged for the treatment of diseases which have up until now been incurable.
A research project is therefore proposed which combines transplantation and gene therapy for the treatment of diabetes mellitus. Indeed, the Applicants have established a .beta. cell line, the INS-I line. This line secretes insulin in response to physiological concentrations of glucose and could, after genetic engineering, be used for transplantation and the "physiological" control of glycemia in insulin-dependent diabetes.
In spite of the therapeutic efforts which have been made in the last decade, the treatment of diabetes remains very unsatisfactory. That is the reason why novel therapies are explored; pancreas or islet transplants are a part thereof (Hellerstrom C, Andersson A, Groth C-G, Sandler S, Jansson L, Korsgren O, Swenne I, Petersson B, Tollemar J, Tyden G--Diabetes Care 11 (Suppl. 1) 45-53 1988) (Pipelleers D. G., Pipelleers-Marichal M, Hannaert J-C, Berghmans M, In't Veld P. A., Rozin J, Van de Winkel M, Gepts W--Diabetes 40:908-919 1991). More than a thousand whole pancreas transplants and a few tens of islet transplants have been performed worldwide. Although promising, these cumbersome techniques raise schematically two types of problem: some immunological, others logistical.
In addition to the problems of tolerance which are inherent to each type of transplant, it should be recalled that diabetes is an autoimmune disease and that the recipient, a diabetic, retains a potential to destroy the .beta. cells transplanted. An absolute need therefore exists to combine an immunosuppressive therapy with the transplant. In order to avoid this immunosuppression, some authors have proposed the transplantation of encapsulated islets (Lacy P, Hegre O. D., Gerasimidi-Vazeo A, Gentile F. T., Dionne K. E.--Science 254:1782-1784 1991) (Chicheportich D, Reach G.--Diabetologia 31:54-57 1988). The essential advantage of the protection and especially of encapsulation is to protect the transplanted tissue from attack by the immune system. However, the low availability of islets makes the preparation of sufficient quantities of the material for therapeutic purposes difficult. Accordingly, considerable efforts have been devoted during the past ten years to establishing .beta. cell lines as models for studying insulin secretion and diabetes. Most of these lines have lost their essential .beta. cell function, namely the response to glucose by secretion of insulin, this loss occurring during subcultures and successive cell cycles. The Applicants have therefore been able to establish a highly differentiated .beta. cell line (INS-I) whose characteristics are very similar to those of normal .beta. cells (Asfari M, Janjic D, Meda P, Li G, Halban P. A., Wollheim C. B.--Endocrinology 130:167-178 1992) and this constitutes the essence of the invention.
Among the remarkable properties of these cells, there may be menti

REFERENCES:
Inoue et. al.. Experimental hybrid islet transplantation: application of polyvinyl alcohol membrane for entrapment of islets. Pancreas vol. 7:562, Jul. 25, 1992.
deVos et. al.. Possible relationship between fibrotic overgrowth of algiinate-polylysine-alginate microencapsulated pancreatic islets and the microcapsule integrity. Transpl. Proc.. vol. 26(2):782-783, Apr. 12, 1994.
Seibers et. al.. Microencapsulated transplantation of allogeneic islets into specifically presensitized recipeints. Transpl. Proc.. vol.26(2):787-788, Apr. 12, 1994.
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Shulman et al., "Homologus Recombination in Hybridoma Cells: Dependence on Time and Fragment Length," Molecular and Cellular Biology, vol. 10, No. 9, pp. 4466-4472, 1990.

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