Chemistry: molecular biology and microbiology – Process of mutation – cell fusion – or genetic modification – Introduction of a polynucleotide molecule into or...
Patent
1998-03-04
2000-06-13
Schwartzman, Robert A.
Chemistry: molecular biology and microbiology
Process of mutation, cell fusion, or genetic modification
Introduction of a polynucleotide molecule into or...
435325, 435354, 435358, 435366, C12N 510, C12N 1563
Patent
active
060748753
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to materials and methods relating to the regulation of polypeptide production in cells, and in particular to the expression of polypeptides in cells so that the rate of polypeptide synthesis and secretion from the cells is linked to their environment, for example the metabolic status of the host into which they are transplanted. The present invention also relates to the use of these cells in the preparation of medicaments for the treatment of conditions that respond to the polypeptides.
BACKGROUND TO THE INVENTION
Type I or insulin-dependent diabetes mellitus is the result of the destruction of the patients' insulin secreting cells, the .beta. cells of the pancreatic islets or islets of Langerhans. This destruction is mediated by an immunological process. Current treatment of type I diabetes consists in multiple daily injections of insulin to correct hyperglycemic episodes. This treatment however does not allows a sufficiently tight regulation of blood glucose levels and this lack of moment to moment control of glycemia leads over time to complications such as kidney failure, neuropathy, cardiac diseases and blindness.
Attempts to better control blood glucose could be achieved by transplantation of insulin secreting .beta. cells. Treatment of type I diabetic patients by transplantation of human pancreatic islets has been shown to be possible. However, treatment of a large number of diabetic patients with human islets is impractical due to the limited availability of pancreas from cadaver donors. Pig islets have been proposed as an alternative source for transplantation, but there is currently no way of reliably preparing sufficient pig islets to treat the millions of diabetic patients.
It has been proposed to use insulin secreting cell lines to overcome these problems. Indeed, the availability of insulin secreting cell lines with a proper control of insulin secretion would appear to present a number of advantages, namely the easy expansion of a cell stock and the precise control of the cells quality. Further, in theory, such cell lines could be generated from previously non insulin-secreting cell lines by genetic engineering. However, so far, the cell lines obtained by this approach secrete insulin constitutively or in a manner inappropriately controlled by variations in glucose concentrations (1).
SUMMARY OF THE INVENTION
Broadly, in a first aspect, the present invention provides cell lines transfected with (a) nucleic acid encoding one or more hormone receptors, the receptors being capable of transmitting a signal, and (b) nucleic acid encoding a desired polypeptide, the nucleic acid encoding the desired polypeptide being under the control of a promoter containing regulatory elements responsive to a signal transmitted by the receptor(s) so that transcription of the nucleic acid encoding the desired polypeptide is modulated by the level of the hormone(s). Thus, these cell lines can then be transplanted into patients so that the production of the polypeptide is controlled by hormone(s) produced by the host, thus linking the production of the polypeptide to the need of the host.
In a further aspect, the present invention includes the compositions comprising these cell lines and their use in the preparation of medicaments for the treatment of conditions that respond to these polypeptides, for example by transplanting the cells into a patient. Examples of conditions that can be treated using this approach include diabetes and obesity. In the former case the desired polypeptide is insulin, and in the latter case, the nucleic acid encodes the ob protein or leptin, or encodes glucogen-like peptide I.
The present invention is based on the realisation that for the treatment of diabetes, a key requirement is that the rate of insulin secretion is regulated according to a patient's metabolic status. Accordingly, in one aspect, the invention provides an approach using genetic engineering to link the rate of insulin synthesis and secretion to the metabolic sta
REFERENCES:
Ko and Takano, 1989, "A Highly Inducible System of Gene Expression by Positive Feedback Production of Glucocorticoid Receptors", DNA 8:127-133.
Waeber et al., 1993, "Neuropeptide Y Expression and Regulation in a Differentiated Rat Insulin-Secreting Cell Line", Endocrinology 133:1061-1067.
Widmann et al., "Signal Transduction by the Cloned Glucagon-like Peptide-1 Receptor: Comparison with Signaling by the Endogenous Receptors of .beta. Cell Lines", Mol. Pharm. 45:1029-1035.
Centre Hospitalier Universitaire Vaudois
Ecole Polytechnique Federale de Lausanne
Elrifi Ivor R.
Prince John T.
Schwartzman Robert A.
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