Gene therapy for obesity

Details Gene therapy for obesity Gene therapy for obesity

1999-04-01

2003-10-07

Fredman, Jeffrey (Department: 1632)

Chemistry: molecular biology and microbiology

Animal cell, per se ; composition thereof; process of...

C435S069100, C435S320100, C435S455000, C536S023100, C536S023500, C514S04400A

Reexamination Certificate

active

06630346

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to methods of gene therapy by vector-assisted delivery of a peptide hormone, and to transgenic non-human mammals so produced. This invention also related to gene therapy for obesity. This invention also relates to vectors useful in this gene therapy.
BACKGROUND OF THE INVENTION
There are numerous potentially therapeutic hormones which are peptides or proteins, including leptin, insulin, calcitonin, erythropoietin, (EPO), growth hormone, interferons, interleukin-2, hemophilia factors, vascular endothelial growth factors such as VEGF, granulocyte-macrophage colony stimulating factor, alpha 1 anti-trypsin, and others. Many have been purified, extensively studied, and even produced recombinantly and administered in a clinical setting. One problem with peptide and/or proteins as therapeutic agents, however, is that they cannot be made into conventional oral dosage forms, as contact with gastric juices will destroy the peptide. Instead, they have to be delivered by injection, intravenously, intranasally or other non-oral routes which are often not convenient for chronic usage, and may add to the expense of the drug therapy. In addition, protein injection is frequently of short duration of action and requires repetitive dosing.
Leptin is a protein expressed by the ob gene. Leptin is secreted by adipose tissue and appears to be both a satiety factor and a regulator of metabolism (Levin et al., 1996
Proc. Natl Acad. Sci. USA
93:1726-1730). Both the mouse gene and its human homologue have recently been identified and sequenced (Zhang et al., 1994
Nature
(London) 372:425-431.)
Mice which are homozygous for the ob gene (oblob) are obese, perhaps due to leptin deficiency. When oblob mice are given daily injections of recombinant protein, their food intake was markedly inhibited and they experienced a reduction in body weight and fat. In lean (i.e. wild-type) mice, daily injections of leptin lead to modest decreases of food intake and body weight. The results for body fat have been confirmatory to the effect of leptin on fat metabolism. (Pelleymounter et al., 1995,
Science
269:540-543; Halaas et al., 1995
Science
269: 543-546; and Campfield et al., 1995
Science
269:546-549).
Obesity in humans is a major disorder associated with mortality, and may result from a number of causes, and at least some may be due to an insufficient amount of leptin produced or resistance. Since leptin is a protein, and vulnerable to breakdown and inactivation by the gastrointestinal system, it cannot be delivered orally. It would be desirable to develop a therapy for leptin delivery for obese patients whose obesity is due, at least in part, to a paucity of leptin or resistance to the sustained peripheral levels.


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