Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1997-02-06
2001-10-09
Criares, Theodore J. (Department: 1617)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
C514S210030, C514S022000, C514S122000, C435S169000
Reexamination Certificate
active
06300327
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to compositions which are useful in potentiating neurotrophin activity, as well as methods for the preparation and use thereof.
Protein growth factors of the neurotrophin family, which includes nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), neurotrophin-4 (NT-4) and neurotrophin-5 (NT-5) regulate nervous system development [Barde, Y-A., “Trophic factors and neuronal survival,”
Neuron
2:1525-1534 (1989); Thoenen, H., “The changing scene of neurotrophic factors,”
Trends Neurosci
14:165-170 (1991); Leibrock, J. et al., “Molecular cloning and expression of brain-derived neurotrophic factor,”
Nature
341:149-152 (1989); Ernfors, P. et al., “Identification of cells in rat brain and peripheral tissues expressing mRNA for members of the nerve growth factor family,”
Neuron
5:511-526 (1990); Hohn, A. et al., “Identification and characterization of a novel member of the nerve growth factor/brain-derived neurotrophic factor family,”
Nature
344:339-341 (1990); Maisonpierre, P. C. et al., “Neurotrophin-3: a neurotrophic factor related to NGF and BDNF,”
Science
247:1446-1451 (1990); Rosenthal, A. et al., “Primary Structure and Biological Activity of a Novel Human Neurotrophic Factor,”
Neuron
4:767-773 (1990); Jones, K. R. and Reichardt, L. F., “Molecular cloning of a human gene that is a member of the nerve growth factor family”,
Proc. Natl. Acad. Sci. USA
87:8060-8064 (1990); Hallbook, F. et al., “Evolutionary studies on the nerve growth factor family reveal a novel member abundantly expressed in Xenopus ovary,”
Neuron
6:845-858 (1991); Berkemeier, L. R. et al., “Neurotrophin-5: a novel neurotrophic factor that activates trk and trkB,”
Neuron
(in press)]. In addition, the neurotrophins are strongly implicated as playing an important role in structural maintenance, plasticity and repair of the adult nervous system [Hefti, F. et al., “Function of neurotrophic factors in the adult and aging brain and their possible use in the treatment of neurodegenerative diseases,”
Neurobiol. Aging
10:515-533 (1989)].
Neurobiological research carried out in recent years has confirmed that development, maintenance of function and regeneration of neurons is profoundly influenced by the neurotrophic factors. These neurotrophins stimulate mechanisms necessary for survival, neurite growth and functions related to transmitter production and release. For example, it has long been known that nerve growth factor (NGF), the first and best characterized neurotrophin, is a neurotrophic factor for peripheral sympathetic and sensory neurons, and more recent findings show that NGF also affects cholinergic neurons in the brain. NGF is required by sympathetic and dorsal root ganglion cells for survival during embryonic and early postnatal life, and is also critical to the normal function of these neuronal types in adult animals. NGF is further implicated in the regulation of a variety of developmental processes such as naturally-occurring cell death, differentiation, process outgrowth and synaptic rearrangement.
Experiments over the last few decades have yielded evidence that NGF regulates a variety of cellular processes important for neuronal function. Administration of pharmacological doses of NGF to rodents results in striking increases in ganglion cell size, axonal branching in the periphery and dendritic arborization as demonstrated by, e.g., intracellular staining techniques. Furthermore, administration of NGF leads to increases in the synthesis of transmitter enzymes and increases in the synthesis of peptides in dorsal root ganglion cells. NGF also exerts effects on preganglionic neurons innervating sympathetic ganglion cells, presumably an indirect effect of its influence on the ganglion cells. Importantly, NGF can prevent death of responsive neurons pursuant to mechanical, chemical and immunological insults. When NGF deprivation is induced by axotomy or administration of antisera, atrophy and reduction in the synthesis of transmitter enzymes occur. Furthermore, when autoimmunity to NGF is induced in rats, guinea pigs and rabbits, there is massive death of sympathetic ganglion cells over a period of several months in animals that generate high antibody titers. Finally, even in adulthood, several neuronal populations in the peripheral and central nervous system respond to transection of their axons by atrophy, reductions in transmitter synthesis and significant degrees of cell death. Taken together, all of these finding in vivo suggest that trophic factors act chronically in the mature animal to maintain normal function. Therefore, trophic deficiency is probably an important mechanism in disease states of adulthood [see Snider, W. D. and Johnson, Jr., E. M., “Neurotrophic Molecules,”
Annals of Neurology
26:489-506 (1989) and references cited therein].
Other neurotrophic molecules characterized thus far influence various other neuronal populations. The existence of different patterns of specificity suggests that there may be a multitude of neurotrophins with different specificities and activities. As the molecules occur in minimal quantities, their isolation is a cumbersome and time-consuming effort.
The discovery of neurotrophic factors has obvious implications with respect to neurodegenerative diseases. Indeed, it has been hypothesized that the lack of neurotrophic factors is responsible for the degeneration of selective neuronal populations as it occurs in Parkinson's disease, Alzheimer's disease and amyotrophic lateral sclerosis, and that application of corresponding neurotrophic factor might prevent neuronal degeneration [Appel, S. H., “A unifying hypothesis for the cause of amyotrophic lateral sclerosis, parkinsonism, and Alzheimer's disease,”
Ann. Neurol
. 10:499-505 (1981)]. In particular, as NGF is a trophic factor for the population of basal forebrain cholinergic neurons which degenerates in Alzheimer's disease, it has been speculated that NGF may be useful in the treatment of this disease.
Classical neuropharmacology attempts to influence mechanisms related to neuronal impulse flow and transmission at the synapse. Currently-used drugs and available pharmacological tools do not affect the structural features of the central nervous system. Moreover, there is a lack of compounds that are able to promote regeneration, plasticity and maintenance of structural integrity of selected neuronal systems. An increased understanding of the properties of neurotrophic factors is virtually certain to lead to the development of a new, structurally-oriented neuropharmacology. In particular, neurotrophic factors shall undoubtedly prove useful in the treatment of neurodegenerative diseases associated with structural disintegration of selected neuronal systems of brain areas.
One of the more exciting features of neurotrophic molecules from a clinical standpoint is their ability to promote cell survival after a variety of insults. For example, it has been shown that NGF has the ability to save neurons that would ordinarily die after mechanical injury. These injuries have been most commonly produced by transecting the axons of sympathetic and dorsal root ganglion cells or basal cholinergic forebrain neurons. Such injuries separate the soma from contact with targets and presumably cause neurons to degenerate because of loss of trophic support, although other mechanisms may be involved. In every circumstance in which axons of a responsive neuronal population have been transected, NGF has saved at least some neurons from degenerating. NGF works after systemic administration for peripheral neurons, as well as after local application to axon tips, and is effective after intraventricular administration for neurons within the central nervous system. Another neurotrophic molecule, FGF, is also effective in some of these same paradigms. This ability to prevent cell death after injury is obviously relevant to the problem of promoting neural regeneration &l
Hefti Franz F.
Knusel Beat J.
Criares Theodore J.
Fulbright & Jaworski L.L.P.
The University of Southern California
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