Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1999-08-19
2004-08-17
Saoud, Christine J. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S014800, C530S326000, C530S329000
Reexamination Certificate
active
06777388
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods and compositions for the modulation of body mass (i.e., weight). More specifically, the present invention relates to the utilization of leptin-like peptides for novel diagnostic and therapeutic implications in homeostasis of body weight and adipose tissue mass.
BACKGROUND OF THE INVENTION
Obesity, defined as an excess of body fat relative to lean body mass, is associated with numerous, important clinical and psychological morbidities, the former includes, but is not limited to: hypertension, elevated blood lipids, and Type II or non-insulin-dependent diabetes mellitus (NIDDM), and decreased life expectancy. The presence and degree of obesity are usually determined by reference to the absolute weight of an individual when compared to age and height matched ideals, or by reference to the individual's body mass index, that is, body weight (in kilograms) divided by height (in meters), compared with age matched ranges. There are approximately 6-10 million individuals with NIDDM in the United States, including 18% of the total population over 65 years of age (see, e.g., Harris, et al., 1987
. Int J Obes
11: 275-283). In addition, approximately 45% of males and 70% of females with NIDDM are obese, and their diabetes is substantially improved or even eliminated by weight reduction (see, e.g., Harris, 1991
. Diabetes Care
14: 639-648). Both obesity and NIDDM are strongly heritable, though few of the predisposing genes have been identified. Hence, the molecular genetic basis of these metabolically related disorders is an important, poorly understood problem.
The assimilation, storage, and utilization of nutrient energy constitute a complex homeostatic system central to survival of metazoa. Among land-dwelling mammals, storage in adipose tissue of large quantities of metabolic fuel in the form of triglycerides is crucial for surviving periods of food deprivation. The need to maintain a fixed level of energy stores without continual alterations in the size and shape of the organism requires the achievement of a balance between energy intake and expenditure. However, the molecular mechanisms that regulate energy balance remain to be elucidated. The isolation of molecules that transduce nutritional information and control energy balance will be critical to an understanding of the regulation of body weight in health and disease.
Examination of the concordance rates of body weight and adiposity amongst mono- and dizygous twins or adoptees and their biological parents have suggested that the heritability of obesity (0.4-0.8) exceeds that of many other traits commonly thought to have a substantial genetic component, such as schizophrenia, alcoholism, and atherosclerosis (see e.g., Stunkard, et al., 1990
. N Engl J Med
322: 1483-1487). Familial similarities in rates of energy expenditure have also been reported (see e. g., Bogardus, et al., 1986
. Diabetes
35: 1-5). Genetic analysis in geographically delimited populations has suggested that a relatively small number of genes may account for the 30-50% of variance in body composition (see e.g., Moll, et al., 1991
. Am. J Hum. Genet
49: 1243-1255).
A major advance in understanding the molecular basis for obesity occurred with the cloning of the ob gene. The mouse obesity (ob) gene encodes an adipose tissue-derived signaling factor for body weight homeostasis. The mouse ob gene encodes a 4.5-kilobase adipose tissue mRNA (see, e.g., Montague, et al., 1997
. Nature
387: 903-908) with a widely conserved 167-amino acid open reading flame and a 21-amino acid secretory signal sequence. The predicted amino acid sequence of the protein product of this gene, leptin (from the Greek leptos, meaning thin), is 84% identical in humans and mice and has features of a secreted protein (see, e.g., Zhang, et al., 1994
. Nature
372: 425). Several recent studies have shown that recombinant ob protein purified from
Escherichia coli
can correct the obesity related phenotypes in ob/ob mice when exogenously administered (see e.g., Campfield, et al., 1995
Science
269: 546; Pellymounter, et al., 1995
. Science
269: 540; Stephens, et al., 1995
. Nature
377: 530). Weight-reducing effects of recombinant leptin were also observed in normal mice and mice with diet-induced obesity.
Interestingly, recent studies have suggested that obese humans and rodents (other than ob/ob mice) are not defective in their ability to produce leptin mRNA or protein and generally produce higher levels than lean individuals (see e.g., Maffei, et al., 1995
. Nature Med
1: 1155; Considine, 1995
. J. Clin. Invest
. 95: 2986; Hamilton, et al., 1995
. Nature Med
. 1: 953). This data suggest that resistance to normal or elevated levels of leptin may be important factors in human obesity.
Leptin is a 16 kDa hormone that is the afferent signal in a negative feedback loop regulating food intake and body weight. The leptin receptor is a member of the cytokine receptor family. Leptin's anorexigenic effect is dependent on binding to the Ob-R
b
isoform of this receptor which encodes a long intracytoplasmic domain that includes several motifs for protein-protein interaction. Ob-R
b
is highly expressed in the hypothalamus suggesting that this brain region is an important site of leptin action. Signal transduction by this class of receptor generally depends on ligand-induced phosphorylation of soluble tyrosine receptor kinases such as Janus kinase (JAK)-1, -2, -3, and tyk2. These kinases, in turn, phosphorylate tyrosine residues on the receptor which serve as docking sites for SH2 proteins. Phosphorylation of SH2 proteins, following receptor-binding, initiates signal transduction. Leptin binds to a homodimer ajar of the Ob-R
b
isoform of its receptor, thus activating JAK2. While Stat3-regulated transcription is activated by leptin in viva, the identity of other components of this signal transduction pathway have not yet been quantitatively identified.
In recent studies, mutation of the mouse ob gene has been demonstrated to result in a syndrome that exhibits pathophysiology which includes: obesity, increased body fat deposition, hyperglycemia, hyperinsulinemia, hypothermia, and impaired thyroid and reproductive functions in both male and female homozygous ob/ob obese mice (see e.g., Ingalis, et al., 1950
. J Hered
41: 317-318). As previously discussed, recent studies have suggested that obese humans and rodents (other than ob/ob mice) are not defective in their ability to produce leptin mRNA or protein and generally produce higher levels than lean individuals. Two distinct mutations of this gene have been identified. One mutant, designated SM/Ckc−+
Dac
ob
2J
/ob
2J
, expresses no leptin mRNA (see, e.g., Lonnqvist, 1996
. Q. J. Med
. 89: 327-332); whereas the other mutation, designated C57BL/6J, overexpresses by 20-fold a mRNA species resulting from a single-base mutation in the ob gene at codon 105. This mutation changes the coding sequence for arginine (Arg)-105 in leptin to a premature stop codon, and causes production of a truncated inactive form of leptin (see, e.g., Zhang, et al., 1994
. Nature
372: 425).
The mouse ob gene (GenBank Accession No. U2242 1) and its human homolog (GenBank Accession No.NM
—
000230) have been cloned (see, e.g., Zhang, et al., 1994
. Nature
372: 425-432). The protein product of this gene, leptin, which has been postulated to act as a blood-borne hormone responsible for weight maintenance, is a 16-kDa plasma protein synthesized and secreted by adipocytes (see e.g., Halaas, et al., 1995
. Science
269: 543-546; Pelleymounter, et al., 1995
. Science
269: 540-543; Weigle, et al., 1995
. J. Clin. Invest
. 96: 2065-2070). The ob/ob mouse phenotype has been attributed to a deficiency in active leptin. A number of laboratories have reported that administration of recombinant leptin to C57BL/6J ob/ob mice, normal lean, or diet-induced obese mice resulted in weight loss through reduced food intake and increased energy expenditure (see e.g., Weigle, et al., 1995
. J Clin Invest
96: 2065-207
Grasso Patricia
Lee Daniel W.
Leinung Matthew C.
Biswas, Esq. Naomi S.
CLF Medical Technology Acceleration Program, Inc.
Elrifi, Esq. Ivor R.
Mintz Levin Cohn Ferris Glovsky and Popeo P.C.
Saoud Christine J.
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