Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1997-09-25
2003-01-14
Kunz, Gary L. (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S350000, C530S402000
Reexamination Certificate
active
06506729
ABSTRACT:
BACKGROUND OF THE INVENTION
The mammalian nervous system comprises a peripheral nervous system (PNS) and a central nervous system (CNS, comprising the brain and spinal cord), and is composed of two principal classes of cells: neurons and glial cells. The glial cells fill the spaces between neurons, nourishing them and modulating their function. Certain glial cells, such as Schwann cells in the PNS and oligodendrocytes in the CNS, also provide a myelin sheath that surrounds neural processes. The myelin sheath enables rapid conduction of impulses along the neuron. In the peripheral nervous system, axons of multiple neurons may bundle together in order to form a nerve fiber. These, in turn, may be combined into fascicles or bundles.
During development, differentiating neurons from the central and peripheral nervous systems send out axons that grow and make contact with specific target cells. In some cases, axons must cover enormous distances; some grow into the periphery, whereas others are confined within the central nervous system. In mammals, this stage of neurogenesis is complete during the embryonic phase of life and neuronal cells do not multiply once they have fully differentiated.
A host of neuropathies have been identified that affect the nervous system. These neuropathies, which may affect neurons themselves or associated glial cells, may result from cellular metabolic dysfunction, infection, exposure to toxic agents, autoimmunity, malnutrition, or ischemia. In some cases, the neuropathy is thought to induce cell death directly. In other cases, the neuropathy may induce sufficient tissue necrosis to stimulate the body's immune/inflammatory system and the immune response to the initial injury then destroys neural pathways.
Attempts to counteract the effects of acute or neurodegenerative lesions of the brain and/or spinal cord have primarily involved implantation of embryonic neurons in an effort to compensate for lost or deficient neural function. However, human fetal cell transplantation research is severely restricted. Administration of neurotrophic factors such as nerve growth factor and insulin-like growth factor also have been suggested to stimulate neuronal growth within the CNS. See, e.g., Lundborg,
Acta Orthop. Scand.
58: 145-169 (1987); U.S. Pat. No. 5,093,317. Administration of neurotrophic factors to the CNS requires bypassing the blood-brain barrier. The barrier may be overcome by direct infusion, or by modifying the molecule to enhance its transport across the barrier, as by chemical modification or conjugation, or by molecule truncation. Schwann cells also have been grafted to a site of a CNS lesion in an attempt to stimulate and maintain growth of damaged neuronal processes. Paino, et al.,
Exp. Neurology
114: 254-257 (1991).
One type of morphoregulatory molecule associated with neuronal cell growth, differentiation and development is the cell adhesion molecule (“CAM”), most notably the nerve cell adhesion molecule (N-CAM). The CAMs are members of the immunoglobulin superfamily. They mediate cell-cell interactions in developing and adult tissues through homophilic binding, i.e., CAM-CAM binding on apposing cells. A number of different CAMs have been identified. Of these, the most thoroughly studied are N-CAM and L-CAM (liver cell adhesion molecules), both of which have been identified on all cells at early stages of development, as well as in different adult tissues. In neural tissue development, N-CAM expression is believed to be important in tissue organization, neuronal migration, nerve-muscle tissue adhesion, retinal formation, synaptogenesis, and neural degeneration. Reduced N-CAM expression also is thought to be associated with nerve dysfunction. For example, expression of at least one form of N-CAM, N-CAM-180, is reduced in a mouse demyelinating mutant. Bhat,
Brain Res.
452: 373-377 (1988). Reduced levels of N-CAM also have been associated with normal pressure hydrocephalus, Werdelin,
Acta Neurol. Scand.
79: 177-181 (1989), and with type II schizophrenia. Lyons, et al.,
Biol. Psychiatry
23: 769-775 (1988). In addition, antibodies against N-CAM have been shown to disrupt functional recovery of injured nerves. Remsen,
Exp. Neurobiol.
110: 268-273 (1990).
Where the damaged neural pathway results from CNS axonal damage, autologous peripheral nerve grafts have been used to bridge lesions in the central nervous system and to allow axons to make contact with their normal target cell. In contrast to CNS neurons, neurons of the peripheral nervous system can extend new peripheral processes in response to axonal damage. This regenerative property of peripheral axons is thought to be sufficient to allow grafting of these segments to CNS axons. Successful grafting appears to be limited, however, by a number of factors, including the length of the CNS axonal lesion to be bypassed, and the distance of the graft sites from the CNS neuronal cell bodies, with successful grafts typically occurring near the cell body.
No satisfactory method exists to repair the damage caused by neuropathies, such as Parkinson's disease (parkinsonism). Parkinson's disease is a syndrome consisting of tremor, rigidity, brady- and hypokinesia, and deficits in equilibrium and posture. The substantia nigra is the principal site of pathology in Parkinson's disease. Pigmented neurons of the substantia nigra project widely and diffusely to the caudate-putamen (corpus striatum) and are specialized to synthesize and release dopamine. There are approximately 500,000 specialized dopaminergic cells in the pars compacta of the substantia nigra of young adults. Symptoms of parkinsonism emerge when 75-80% of the dopaminergic innervation is destroyed. Patients with Parkinson's disease respond to dopamine replacement therapy. Unfortunately, the efficacy of dopamine replacement therapy decreases progressively with continued degeneration of the nigrostriatal dopaminergic pathway. Accordingly, there is a need in the art for treatments of neurological disorders, such as Parkinson's disease, and related deficits in neural function.
SUMMARY OF THE INVENTION
The present invention provides methods and compositions for treating Parkinson's disease, including methods for enhancing the survival of neural cells. In one aspect, the invention features compositions and therapeutic treatment methods comprising administering to a mammal a therapeutically effective amount of a morphogenic protein (“morphogen”), as defined herein, upon diagnosis of Parkinson's disease, or upon detecting degeneration of the nigrostriatal pathway prior to the appearance of symptoms of parkinsonism (i.e., when less than 75-80% of the dopaminergic innervation is destroyed).
In a preferred embodiment, methods of the invention for treating Parkinson's disease comprise administering a morphogen comprising a dimeric protein having an amino acid sequence selected from the group consisting of a sequence having 70% homology with the C-terminal seven-cysteine skeleton of human OP-1 (amino acids 330-341 of SEQ ID NO: 2); a sequence having greater than 60% amino acid sequence identity with human OP-1; generic sequence 7 (SEQ ID NO: 4); generic sequence 8 (SEQ ID NO: 5); generic sequence 9 (SEQ ID NO: 6); generic sequence 10 (SEQ ID NO: 7); and OPX (SEQ ID NO: 3); wherein the morphogen stimulates production of N-CAM or L1 isoform by an NG108-15 cell in vitro. The same or similar methods are contemplated to restore neural cell function in a mammal having Parkinson's disease. Administering one of the aforementioned morphogens also provides a prophylactic function. Such administration has the effect of preserving neural cell function in a mammal having, or at risk of having, Parkinson's disease. Also according to the invention, morphogen administration preserves the integrity of the nigrostriatal pathway, as well as other pathways, in the brain. Prophylactically, morphogens of the invention also prevent degeneration of the nigrostriatal pathway or loss of functional activity associated with
Cohen Charles M.
Oppermann Hermann
Pang Roy H. L.
Rueger David C.
Sampath Kuber T.
Curis, Inc.
Gucker Stephen
Kunz Gary L.
Ropes & Gray
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