Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1996-05-03
2001-03-27
Jones, Dwayne C. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S021800, C514S003100, C530S303000, C530S311000, C530S399000
Reexamination Certificate
active
06207640
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to a method for increasing the growth rates of human patients having partial growth hormone insensitivity syndrome.
2. Description of Background and Related Art
Most children with significant short stature do not have growth hormone (GH) deficiency as classically defined by the GH response to provocative stimuli. Once known causes of short stature have been excluded, these patients are classified with various terms, including familial short stature, constitutional delay of growth, or “idiopathic” short stature (ISS). Some of these children may not reach their genetic potential for height, although results from large-scale longitudinal studies have not been reported. Since there are so many factors that contribute to normal growth and development, it is likely that patients with ISS are heterogeneous with regard to their etiology of short stature. Despite not being classically GH deficient, most children with ISS respond to treatment with GH, although not as well.
Many investigators have searched for disturbances in spontaneous GH secretion in this set of patients. One hypothesis suggests that some of these patients have inadequate secretion of endogenous GH under physiologic conditions, but are able to demonstrate a rise in GH in response to pharmacologic stimuli, as in traditional GH stimulation tests. This disorder has been termed “GH neurosecretory dysfunction,” and the diagnosis rests on the demonstration of an abnormal GH pattern on prolonged serum sampling. Numerous investigators have reported results of such studies, and have found this abnormality to be only occasionally present. Other investigators have postulated that these patients have “bioinactive GH;” however, this has not yet been demonstrated conclusively.
When the GH receptor (GHR) was cloned, it was shown that the major GH binding activity in blood was due to a protein which derives from the same gene as the GHR and corresponds to the extracellular domain of the full-length GHR. Most patients with growth hormone insensitivity (or Laron) syndrome (GHIS) lack growth hormone receptor binding activity and have absent or very low GH-binding protein (GHBP) activity in blood. Such patients have a mean height standard deviation score (SDS) of about −5 to −6, are resistant to GH treatment, and have increased serum concentrations of GH and low serum concentrations of insulin-like growth factor (IGF-I). They respond to treatment with IGF-I. In patients with defects in the extracellular domain of the GHR, the lack of functional GHBP in the circulation can serve as a marker for the GH insensitivity.
There is a subclass of patients with ISS having low GHBP in their blood who have a mean height SDS intermediate between patients with complete GHIS (Laron syndrome) and normal children, and who respond somewhat, but not completely, to GH treatment. This class of patients can be characterized as having partial GHIS.
It is an object of the present invention to identify a subset of patients with ISS who exhibit partial GHIS and do not have complete GHIS or Laron syndrome.
It is another object to treat this identified subset of patients so that they attain ultimate height consistent with their genetic potential as determined by the mid-parental target height.
These and other objects will be apparent to those of ordinary skill in the art.
SUMMARY OF THE INVENTION
Accordingly, in one aspect, the present invention provides a method for increasing the growth rate of a human patient having partial GHIS comprising administering an effective amount of GH to said patient, whereby said patient has a height less than about −2 standard deviations below normal for age and sex, has a serum level of high-affinity GHBP that is at least 2 standard deviations below normal levels, has a serum level of IGF-I that is below normal mean levels, and has a mean or maximum stimulated serum level of GH that is at least normal, wherein the patient does not have Laron syndrome. Preferably, the GH is human recombinant GH.
In another aspect, the invention provides a method for increasing the growth rate of a human patient having partial GHIS comprising administering an effective amount of IGF-I (preferably human recombinant IGF-I) to said patient, whereby said patient has a height less than about −2 standard deviations below normal for age and sex, has a serum level of high-affinity GHBP that is at least 2 standard deviations below normal levels, has a serum level of IGF-I that is below normal mean levels, and has a mean or maximum stimulated serum level of GH that is at least normal, wherein the patient does not have Laron syndrome.
In a further aspect, the invention supplies a method for increasing the growth rate of a human patient having partial GHIS comprising administering amounts of IGF-I and GH to said patient which amounts are effective in combination, whereby said patient has a height less than about −2 standard deviations below normal for age and sex, has a serum level of high-affinity GHBP that is at least 2 standard deviations below normal levels, has a serum level of IGF-I that is below normal mean levels, and has a mean or maximum stimulated serum level of GH that is at least normal, wherein the patient does not have Laron syndrome.
In a still further aspect, the present invention provides a method for increasing the growth rate of a human patient having partial GHIS whereby said patient has a heterogeneous (intracellular and/or extracellular) GHR gene defect comprising administering an effective amount of GH and/or IGF-I to said patient. Preferably, the GH is human recombinant GH and the IGF-I is human recombinant IGF-I.
In a still further aspect, the invention provides a method for increasing the growth rate of a human patient having partial GHIS comprising detecting whether the patient has a heterogeneous (intracellular and/or extracellular) GHR gene defect, and if so, administering an effective amount of GH and/or IGF-I to said patient.
REFERENCES:
patent: 5187151 (1993-02-01), Clark et al.
patent: 5646113 (1997-07-01), Attie et al.
patent: 5824642 (1998-10-01), Attie et al.
patent: 95/27495 (1995-10-01), None
Mauras et al., “IGF-K Deficiency and Growth Failure: Association with Mutations in the Intracellular Domain of the Growth Hormone Receptor Gene,” Joint Meeting of the American Pediatric Society and the Society for Pediatric Research, Washington, DC, (May 6-10, 1996)Pediatric Research39(4 Part 2):93A Abstract No. 541 (1996).
Shimasaki et al., Progress in Growth Factor Res., vol. 3, pp 243-66 (1991).
Attie Kenneth M.
Carlsson Lena M. S.
Gesundheit Neil
Goddard Audrey
Delacroix-Muirheid C.
Genentech Inc.
Jones Dwayne C.
Knobbe Martens Olson & Bear LLP
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