Multicellular living organisms and unmodified parts thereof and – Nonhuman animal – Transgenic nonhuman animal
Reexamination Certificate
1998-07-30
2001-09-11
Martin, Jill D. (Department: 1632)
Multicellular living organisms and unmodified parts thereof and
Nonhuman animal
Transgenic nonhuman animal
C536S023100, C435S320100, C435S325000, C435S455000, C424S184100, C530S309000, C530S399000
Reexamination Certificate
active
06288301
ABSTRACT:
BACKGROUND OF THE INVENTION
This invention relates to treatment of diabetes mellitus by effecting the differentiation of pancreatic islet precursor cells into mature insulin-producing cells by the combined synergistic stimulation by a gastrin/cholecystokinin (CCK) receptor ligand, particularly gastrin, and an epidermal growth factor (EGF) receptor ligand, particularly transforming growth factor alpha (TGF&agr;).
The pancreatic islets develop from endodermal stem cells that lie in the fetal ductular pancreatic endothelium, which also contains pluripotent stem cells that develop into the exocrine pancreas. Teitelman, G. and J. K. Lee,
Developmental Biology,
121: 454-466 (1987); Pictet, R. and W. J. Rutter,
Development of the embryonic endocrine pancreas, in Endocrinology, Handbook of Physiology
, ed. R. O.Greep and E. B. Astwood (1972), American Physiological Society: Washington D.C., p. 25-66. Islet development proceeds through discrete developmental states during fetal gestation which are punctuated by dramatic transitions. The initial period is a protodifferentiated state which is characterized by the commitment of these pluripotent stem cells to the islet cell lineage, as manifested by the expression of insulin and glucagon. These protodifferentiated cells comprise a population of committed islet precursor cells which express only low levels of islet specific gene products and lack the cytodifferentiation of mature islet cells. Pictet, R. and W. J. Rutter, supra. Around day 16 in mouse gestation, the protodifferentiated pancreas begins a phase of rapid growth and differentiation characterized by cytodifferentiation of islet cells and a several hundred fold increase in islet specific gene expression. Histologically, islet formation (neogenesis) becomes apparent as proliferating islets bud from the pancreatic ducts (nesidioblastosis). Just before birth the rate of islet growth slows, and islet neogenesis and nesidioblastosis becomes much less apparent. Concomitant with this, the islets attain a fully differentiated state with maximal levels of insulin gene expression. Therefore, similar to many organs, the completion of cellular differentiation is associated with reduced regenerative potential.
Since differentiation of protodifferentiated precursors occurs during late fetal development of the pancreas, the factors regulating islet differentiation are likely to be expressed in the pancreas during this period. One of the genes expressed during islet development encodes the gastrointestinal peptide, gastrin. Although gastrin acts in the adult as a gastric hormone regulating acid secretion, the major site of gastrin expression in the fetus is the pancreatic islets. Brand, S. J. and P. J. Fuller,
J. Biol Chem.,
263:5341-5347 (1988). Expression of gastrin in the pancreatic islets is transient. It is confined to the period when protodifferentiated islet precursors form differentiated islets. Although the significance of pancreatic gastrin in islet development is unknown, some clinical observations suggest a role for gastrin in this islet development as follows. For example, hypergastrinemia caused by gastrin-expressing islet cell tumors and atrophic gastritis is associated with nesidioblastosis similar to that seen in differentiating fetal islets. Sacchi, T. B., et al.,
Virchows Archiv B,
48:261-276 (1985); and Heitz, P. U., et al.,
Diabetes,
26:632-642 (1977). Further, an abnormal persistence of pancreatic gastrin has been documented in a case of infantile nesidioblastosis. Hollande E., et al.,
Gastroenterology,
71:255-262 (1976). However, in neither observation was a causal relationship established between the nesidioblastosis and gastrin stimulation.
Citation of a reference herein shall not be construed as an admission that such reference is prior art to the present invention.
SUMMARY OF THE INVENTION
The invention provides a method for treating diabetes mellitus by administering a composition providing a gastrin/CCK receptor ligand, e.g. gastrin, and an EGF receptor ligand, e.g. TGF&agr;, in an amount sufficient to effect differentiation of pancreatic islet precursor cells to mature insulin-secreting cells. The composition can be administered systemically or expressed in situ by cells supplemented with a nucleic acid fusion construct in an expression vector. The fusion construct includes a preprogastrin peptide precursor coding sequence and can also include a coding sequence for an EGF receptor ligand.
In summary, the studies reported below demonstrate that complete islet cell neogenesis has now been reactivated in vivo in mammals in the ductular epithelium of the adult pancreas by stimulation with a gastrin/CCK receptor ligand, such as gastrin, and an EGF receptor ligand, such as TGF&agr;. These studies demonstrate and confirm that both types of growth factors are required to achieve the envisioned objective, neither one alone is sufficient. Studies are reported on the transgenic over-expression of TGF&agr; and gastrin in the pancreas which elucidate the role of pancreatic gastrin expression in islet development and indicate that TGF&agr; and gastrin each play a role in regulating islet development.
Thus, regenerative differentiation of residual pluripotent pancreatic ductal cells into mature insulin-secreting cells has now become a viable clinical option for the treatment of diabetes mellitus, particularly juvenile onset diabetes, by therapeutic administration of this combination of factors or compositions which provide for their in situ expression within the pancreas.
REFERENCES:
patent: 5587309 (1996-12-01), Rubin et al.
patent: 5885956 (1999-03-01), Nardi et al.
patent: WO 95/19785 (1995-05-01), None
Merriam Webster's Collegiate Dictionary, 10th ed. Merriam-Webster, Inc: Springfield, MA., p. 318, 1997.*
Ledley et al. Pharmacological Research. 13(11): 1595-1614, Nov. 1996.*
Miller et al. FASEB 9: 190-199, Feb. 1996.*
Mulligan, RC. Science. 260.: 926.9, May 1993.*
Eck et al.Chapter 5. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 9th Ed. McGraw-Hill, 1995.*
Verma et al. Nature. 389: 239-242, Sep. 1997.*
Selden et al. Nature. 321: 525-528, May 1986.*
Ito et al. Proc Natl Acad Sci USA. 81(15): 4662-6, Aug. 1984.*
Brand et al. J. Biol. Chem. 263(11): 5341-47, Apr. 1988.*
Brand et al. J. Biol. Chem. 263: 16597-16603, Nov. 1988.*
Sandgren et al. Cell. 61: 1121-1135, Jun. 1990.*
Baldwin et al. Cancer Research. 52:2261-2267, Apr. 1992.*
Baldwin and Zhang,Cancer Research(1992) 52: 2261-2267.
Durrant et al.,British J. Cancer(1991) 63: 67-70.
Kappel et al.,Current Opinion in Biotechnology(1993) 3: 548-553.
Korc, Murray,J. Clin. Invest.(Sep. 1993) 92: 1113-1114.
Ohlsson et al.,Scand. J. Gastroenterol(1989) 24: 693-704.
Osopkoski et al.,Diabetologia(Aug. 1996) 39: A63.
Prowse et al.,AJEBAK(1982) 60(Pt. 6): 619-627.
Rosenberg and Vinik,Pancreatic Islet Cell Regeneration and GrowthNew York: Plenum Press, 1992.
Selden et al.,Nature(1986) 321: 525-528.
Simeonovic et al.,Diabetes Research and Clinical Practice(1990) 8: 275-281.
Strojek and Wagner,Genetic Engineering: Principles and Methods (1988). 10: 221-246.
Wang et al.,Diabetologia(Dec. 1995) 38: 1405-1411.
Wang et al.,Diabetologia(Aug. 1996) 39: A63.
Wang et al.,The Journal of Clinical Investigation, Inc.(Sep. 1993). 92: 1349-1356.
Fraga et al. (Apr. 1998)Transplanation 65(8):1060-1066.
Brand Stephen J.
Nardi Ronald V.
Martin Jill D.
Paras, Jr. Peter
Rae-Venter Barbara
Rae-Venter Law Group P.C.
Waratah Pharmaceuticals, Inc.
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