Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing
Reexamination Certificate
2001-07-13
2004-09-28
Kemmerer, Elizabeth (Department: 1647)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
C514S002600
Reexamination Certificate
active
06797264
ABSTRACT:
FIELD OF INVENTION
The present invention relates to use of substances that upon administration to a patient will lead to increased concentrations of growth hormone for the production of medicinal products.
The present invention also relates to a method for treatment of abnormal conditions affecting neural stem cells or progenitor cells.
BACKGROUND OF THE INVENTION
The result of traumatic, asfyxial, hypoxic, ischemic, toxic, infectious, degenerative or metabolic insults to the central nervous system (CNS) of man may involve a certain degree of damage in several different cell types. Damage to the brain by trauma, asphyxia, toxins, ischemia or infections are frequently causing neurological and cognitive deficits. Degenerative diseases may cause loss of specific populations of cells. For instance Parkinson's disease is associated by specific loss of dopaminergic neurons in the Substantia nigra, similarly, multiple sclerosis is associated with loss of myelin and oligodendrocytes. Other examples of degenerative disorders caused by selective loss of a specialized type of neurons is Alzheimer's disease associated with loss of cholinergic neurons. There are many other instances in which CNS injury or disease can cause damage to oligodendroglia, astroglia or neuronal cells.
Furthermore, axonal regeneration and sprouting after injury to axons in the CNS white mater tracts and injury to the spinal cord has been shown to be inhibited by surface molecules expressed by oligodendrocytes.
Progenitor cells have been grown and propagated with growth factors like epidermal growth factor (EGF), which is a substance belonging to a different class than GH.
In general, replacement of neurons following degeneration or damage is not a characteristic of the mammalian brain. Neuronal loss is thus considered permanent. Prolonged postnatal neurogenesis has been described in the granule cell layer of the hippocampal formation (Altman, J., and Das, G. D., J. Comp. Neurol. 124: 319-335 (1965); Altman, J. and Das, G. D. Nature 214: 1098-1101 (1967); Caviness, V. S. jr., J. Comp Neurol. 151: 113-120 (1973); Gueneau, G., Privat, A., Drouet, J., and Court, L., Dev. Neurosci. 5, 345-358 (1982); Eckenhoff, M. F., and Rakic, P., J. Neurosci. 8: 2729-2747 (1988)). Neurogenesis has recently been shown to persist well into adulthood in man (Eriksson, P. S., Perfilieva, E., Björk-Eriksson, T., Alborn, A., Nordborg, C., Peterson, D. A., Gage, F. H., Nature Med. in press). Neuronal progenitor cells reside in the subgranular zone (SGZ) of the dentate gyrus where they continuously proliferate, migrate into the granulae cell layer and differentiate into granule cells (Kuhn, H., Dickinson-Anson, H., and Gage, F. H., J. Neurosci. 16: 2027-2033 (1996); Cameron, H. A., Woolley, C. S., McEwen, B. S., and Gould, E., Neuroscience 56: 337-344 (1993); Seki, T. and Arai, Y., J. Neurosci. 13: 2351-2358 (1993)). These newborn neurons in the granule cell layer express markers of differentiated neurons and have morphological characteristics corresponding to differentiated granulae cells (Kaplan, M. S. and Bell, D. H., J. Neurosci. 4: 1429-1441 (1984); Cameron, H. A., Woolley, C. S., McEwen, B. S. and Gould, E. Neuroscience 56: 337-344 (1993); Cameron, H. A., Woolley, C. S., and Gould, E., Brain Res. 611: 342-346 (1993)). Furthermore, they establish axonal processes into the mossy fiber pathway and form synaptic connections with their targets in hippocampus CA3 (Seki, T. and Arai, Y., J. Neurosci. 13: 2351-2358 (1993); Stanfield, B. B. and Trice, J. E. Exp. Brain Res. 72: 399-406 (1988)). The hippocampus is associated with spatial learning and memory (McNamara, R. K, and Skelton, R. W., Brain Res. Rev. 18: 33-49 (1993)). The proliferation of progenitor cells can be influenced by the administration of n-methyl-d-aspartate (NMDA) receptor antagonists or by the removal of the adrenal glands (Cameron, H. A. and Gould, E. Neuroscience 61: 203-209 (1994); Cameron, H. A., Tanapat, P., and Gould, E., Neuroscience 82: 349-354 (1998)). Plasticity is reduced with increasing age, and recent studies have demonstrated that proliferation of progenitor cells also is decreased but not completely abolished with age (Kuhn, H., Dickinson-Anson, H., and Gage, F. H., J. Neurosci. 16: 2027-2033 (1996)). Stem cells isolated from the adult rodent brain has recently been transplanted into the brain of adult animals where they differentiate into cells with neuronal characteristics (Suhonen, J. O., Peterson, D. A., Ray, J. And Gage, F. H., Nature 383: 624-627 (1996)).
Furthermore, neurogenesis in the dentate gyrus in young mice has been shown to be facilitated by enriched environments. It was shown that exposure to enriched environments leads to an increased number of surviving newly formed granulae cell neurons and an increased total number of neurons in the dentate gyrus (Kempermann, G., Kuhn, H. G., and Gage, F. H., Nature 386: 493-495 (1997)).
SUMMARY OF THE INVENTION
It has now been found that by using growth hormone, or an analogue thereof, or another substance leading to increased concentrations of growth hormone or analogues thereof, it is possible to modulate the proliferation and/or differentiation of neural stem cells and progenitor cells from the adult CNS. The present invention thus provides new possibilities to treat injuries to or diseases of the central nervous system that predominantly affect oligodendroglia, astroglia or neuronal cells by modification of proliferation cell genesis and/or differentiation of neuronal stem cells or progenitor cells in the central nervous system.
It has also been found that it is possible to control the propagation in vitro of stem cells, progenitorcells and other cells, especially cells derived from the central nervous system, with the potential to generate neurons, astrocytes or oligodendrocytes. Such cells may e.g. be used for therapeutic purposes in patients.
Thus, the present invention relates to the use of a substance that upon administration to a patient will lead to an increased concentration of growth hormone or a functionally equivalent analogue thereof for the production of a medicinal product for treatment of an abnormal condition affecting neural stem cells and/or progenitor cells.
The invention also relates to a method for treatment of an abnormal condition affecting neural stem cells and/or progenitor cells, wherein a pharmaceutically active amount of a substance that will lead to an increased concentration of growth hormone or a functionally equivalent analogue thereof is administered to a patient.
Furthermore, the invention relates to a method of inducing lineage determination, propagating and/or inducing or maintaining the genesis of neurons, oligodendrocytes, astroglial cells from progenitor cells, stem cells and/or cells derived from said cells by administration of an effective amount of growth hormone or a functionally equivalent analogue thereof to stem cells, progenitor cells, neurons astroglial cells and/or oligodendrocytes in vitro.
Another aspect of the invention relates to abnormal conditions in the CNS due to too high concentrations of growth hormone in the CNS.
The invention thus also relates to the use of a substance that upon administration to a patient will lead to a decreased concentration of growth hormone or a functionally equivalent analogue thereof for the production of a medicinal product for treatment of an abnormal condition affecting stem cells, progenitor cells and/or cells derived from stem cells or progenitor cells, as well as to a method of reducing the genesis of oligodendrocytes, neurons, astroglial cells from progenitor cells or stem cells in, or derived from, the central or periferal nervous system in a patient, wherein a pharmaceutically effective amount of a substance that will lead to a decreased concentration of growth hormone or a functionally equivalent analogue thereof is administered to said patient. The characterizing features of the invention will be evident from the following description and the appended is claims.
DETAILED DESCRIPTION OF THE INVENT
Burns Doane , Swecker, Mathis LLP
Cellartis AB
Kemmerer Elizabeth
Nichols Christopher James
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