Drug – bio-affecting and body treating compositions – Lymphokine
Reexamination Certificate
2001-02-27
2003-05-27
Mertz, Prema (Department: 1646)
Drug, bio-affecting and body treating compositions
Lymphokine
C514S002600, C514S008100, C514S012200
Reexamination Certificate
active
06569419
ABSTRACT:
BACKGROUND OF THE INVENTION
The peripheral nervous system (PNS) serves as a bridge between the environment and the central nervous system (CNS). The PNS is comprised of primary afferent neurons, which sends information from sensory receptors to the CNS, somatic motor neurons, which transmit electrical stimuli from the CNS to voluntary muscles, and autonomic motor neurons, which transmit electrical stimuli to cardiac muscle, smooth muscle or glands. A neuron generally has a cell body, and an axon, which is a long nerve cell process extending from the cell body that is capable of rapidly conducting nerve impulses over long distances so as to deliver signals to cells. The axons of many vertebrate neurons are insulated by a myelin sheath, which greatly increases the rate at which an axon can conduct an action potential. Schwann cells are responsible for myelinating nerve cells in the peripheral nervous system. The Schwann cells wrap layer upon layer of their own plasma membrane in a tight spiral around the axon thereby insulating the axonal membrane so that almost no current leaks across it. Unmyelinated axons in the PNS are nonetheless embedded in Schwann cells although they are not ensheathed by myelin.
A number of neuropathies of the PNS are associated with demyelination or failure of the Schwann cells to properly ensheath the axons of the PNS. They are diabetic neuropathy, Guillain-Barré disease (acute demyelinating polyneuropathy), chronic inflammatory demyelinating polyradiculoneuropathy (CIPD), and HIV inflammatory demyelinating disease. Also axon damage due to physical trauma may result in demyelination of the PNS. Thus, there is a need to discover agents that can be used to promote the production of myelin by Schwann cells.
DESCRIPTION OF THE INVENTION
The present invention fills this need by providing for a method for promoting production of myelin or P zero protein by Schwann cell comprising bringing a Zcyto7 polypeptide or IL-17 into contact with Schwann cells. Examples of Zcyto7 polypeptides are the polypeptides of SEQ ID NOs: 2, 7, and 9-28.
Preferably, the mammal treated will be a human and the Zcyto7 will be of the human allotypes. Preferably, the Zcyto7 will be administered in an amount of about 0.1 to 100 micrograms (&mgr;g) per kilogram of body weight.
The teachings of all of the references cited in the present specification are incorporated in their entirety herein by reference.
Definitions
The term “effective amount” as used herein regarding the effective amount of Zcyto7 administered in accordance with the present invention means an amount of Zcyto7 that causes increased expression of myelin by Schwann cells. The effective amount of Zcyto7 or IL-17 to be administered is from 0.1 &mgr;g to 1 mg of Zcyto7 or IL-17 per kilogram of body weight per day. More preferably, the effective amount is from 1 &mgr;g to 500 &mgr;g of Zcyto7 or IL-17 per kilogram of body weight. Zcyto7 should be administered daily until the symptoms of neuropathy dissipate.
The term “allelic variant” denotes any of two or more alternative forms of a gene occupying the same chromosomal locus. Allelic variation arises naturally through mutation, and may result in phenotypic polymorphism within populations. Gene mutations can be silent (no change in the encoded polypeptide) or may encode polypeptides having altered amino acid sequence. The term allelic variant is also used herein to denote a protein encoded by an allelic variant of a gene.
Zcyto7 and a method for making Zcyto7 polypeptides have been disclosed in International Patent Application No. PCT/US98/08212, Publication No. WO 98/49310.
Introduction
The present invention is based upon the discovery that Zcyto7 or IL-17 can induce the production of myelin by Schwann cells. The present invention is also based upon the discovery that Zcyto7 can induce the production of protein zero by Schwann Cells. Protein zero is a major structural protein of peripheral myelin, and is a homophilic immunoglobulin cell adhesion molecule, which mediates adhesion of Schwann cell membranes as they enwrap axons and generate compact myelin, Spiryda L. B.,
J. Neurosci, Res.
54: 137-146 (1998).
The axons of many vertebrate neurons are insulated by a myelin sheath, which greatly increases the rate at which an axon can conduct an action potential. Schwann cells, which are supporting or glial cells, form myelin in the peripheral nerves. The Schwann cells wrap layer upon layer of their own plasma membrane in a tight spiral around the axon, thereby insulating the axonal membrane so that almost no current leaks across it. The sheath is interrupted at regularly spaced intervals called the ‘nodes of Ranvier’, where almost all the Na
+
channels in the axon are concentrated. Because the ensheathed portions of the axon membrane are so well insulated, a depolarization of the membrane at one node almost immediately spreads passively to the next node. Thus, an action potential propagates along a myelinated axon by jumping from node to node, a process called salutatory conduction. This type of conduction has two main advantages: action potentials travel faster, and metabolic energy is conserved because the active excitation is confined to the small regions of axonal plasma membrane at nodes of Ranvier. Conduction in myelinated axons is characterized by a rapid electronic conduction (because of the decreased time constant for conduction) with little decrement (because of the increased length constant) between the nodes of Ranvier. Only at the nodes is the action potential regenerated. A myelination of an axon increases electronic conduction velocity by sevenfold.
Myelinated axons are also more efficient metabolically than nonmyelinated axons. The sodium-potassium pump extrudes the sodium that enters and re-accumulates the potassium that leaves the cell during action potentials. In a myelinated axon, ionic currents are restricted to the small fraction of the membrane surface at the nodes of Ranvier. For this reason fewer Na
+
and K
+
ions traverse a unit area of membrane, and less ion pumping is required to maintain Na
+
and K
+
gradients.
The present invention is a method for inducing the expression of myelin or Protein zero by Schwann cells. Thus, Zcyto7 can be administered to treat a number of demyelinating PNS neuropathies, or to induce the production of myelin around regenerating peripheral nerve cells that have been injured by trauma.
Those skilled in the art will recognize that the sequences disclosed in SEQ ID NOS: 1, and 2 represent a single allele of the human Zcyto7. One can clone allelic variants of these sequences by probing cDNA or genomic libraries from different individuals according to standard procedures.
Acute Demyelinating Polyneuropathy
An example of a demyelinating disease of the PNS is acute demyelinating polyneuropathy. This acute inflammatory polyneuropathy, also known as Guillain-Barré syndrome (GBS), occurs in all parts of the world and in all seasons. It affects children and adults of all ages and both sexes. A mild respiratory or gastrointestinal infection precedes the neuritic symptoms by 1 to 3 weeks in about 60 percent of the patients. Other less common antecedent events include surgical procedures, viral exanthems and other viral illnesses such as cytomegalovirus, Epstein-Barr virus, human immunodeficiency virus (HIV), bacterial infections, e.g.,
Mycoplasma pneumoniae
, Lyme disease and particularly
Campylobacter jejuni
, and lymphoma, particularly Hodgkin's disease.
Symptomatology
The major clinical manifestation of GBS is weakness, which evolves, more or less symmetrically, over a period of several days or a week or two. Proximal as well as distal muscles of the limbs are involved, usually the lower extremities before the upper trunk, intercostals, neck, and cranial muscles are affected later. The weakness can progress to total motor paralysis with death from respiratory failure within a few days. More than half of the patients complain of pain and an aching discomfort in the muscles, mainly those of the hip
Moore Emma E.
Novak Julia E.
Lunn, Esq. Paul G.
Mertz Prema
ZymoGenetics Inc.
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