Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,...
Reexamination Certificate
1998-10-28
2003-04-15
Allen, Marianne P. (Department: 1631)
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
C424S141100, C424S172100
Reexamination Certificate
active
06548061
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to compositions and their methods of use in promoting the growth and/or regeneration of neurological tissue within the central nervous system (CNS).
BACKGROUND
CNS Damage
Approximately 1,100 new spinal cord injuries occur each year in Canada; over 10,000 per year occur in the United States. These numbers are five times higher if one also includes patients suffering brain damage involving inhibition to neural growth following traumatic brain injury. The number of patients with chronic spinal cord injuries in North America is in the order of 300,000. Again, this number is five times higher if one includes patients suffering from brain damage involving inhibition to neural growth following traumatic brain injury.
Spinal cord injuries often result in a permanent loss of voluntary movement below the site of damage. Mostly young and otherwise healthy persons become paraplegic or quadriplegic because of spinal cord injuries. There are an estimated 200,000 quadriplegics in the United States. Given the amount of care required, it is not difficult to envision how health care costs associated with caring for patients with central nervous system (CNS) damage is well over $10 billion a year for North America.
The CNS (the brain and the spinal cord) is comprised of neurons and glia, such as astrocytes, microglia, and oligodendrocytes. Neurons typically have two types of processes: dendrites, which receive synaptic contact from the axons of other neurons; and axons, through which each neuron communicates with other neurons and effectors. The axon of a CNS neuron is wrapped in a myelin sheath.
In higher vertebrates, axons within the CNS possess a limited capacity for repair after injury. Axotomized neurons of the adult mammalian CNS fail to exhibit substantial axonal regeneration, in contrast to neurons within the embryonic or neonatal CNS or within the adult peripheral nervous system (PNS) (Saunders et al., (1992)
Proc. R. Soc. Lond. B. Biol
. 250:171-180; Schwab and Bartoldi (1996)
Physiol. Rev
. 76:319-370; Steeves et al., (1994)
Prog. Brain Res
. 103:243-262). In fact, complete CNS axonal disruption is likely to preclude recovery. Although axotomized fibers proximal to the neuronal cell body initiate regenerative growth, this is subsequently aborted within a short distance (1-2 mm) and is often followed by retrograde degeneration. Although CNS axons will not regrow in the environment of the adult spinal cord, peripheral nerve grafts into the CNS provide a favorable environment through which CNS axons will anatomically regenerate (May et al.,
Cajal's Degeneration and Regeneration of the Nervous System, History of Neuroscience Series
#5 (NY and Oxford: Oxford Univ. Press, 1991) at 769). These findings indicate that adult CNS neurons retain intrinsic growth properties and, given favorable environmental conditions, are capable of successfully reactivating growth programs.
Current Treatments of Spinal Cord Injuries
A number of current therapies exist for the treatment of spinal cord injuries. Interventional therapies, including opiate antagonists, thyrotropin-releasing hormone, local cord cooling, dextran infusion, adrenergic blockade, corticosteroids, and hyperbaric oxygen have been utilized, but are of questionable clinical value.
Peripheral nerve transplants have been suggested as bridges across CNS lesions (David and Aguayo (1981)
Science
214:931-933; Houle (1991)
Exp. Neurol
. 113:1-9; Richardson et al., (1984)
J. Neurocytol
. 13:165-182; Richardson et al., (1980)
Nature
284:264-265; Xu et al., (1995)
Exp. Neurol
. 138:261-276; Ye and Houle (1997)
Exp. Neurol
. 143:70-81). Olfactory ensheathing cell transplants have been used recently to promote the regeneration of injured corticospinal projections in the rat (Li et al., (1997)
Science
277:2000-2002). A recent study (Cheng et al., (1996)
Science
273:510-513) employed a combinatorial approach that extended earlier work (Siegal et al., (1990)
Exp. Neurol
. 109:90-97): after transection of the adult rat spinal cord, peripheral grafts were used to connect white matter tracts to central gray matter in such a way as to direct regenerating fibers out of an inhibitory environment and into the more permissive gray matter. U.S. Pat. No. 5,650,148 and 5,762,926 describe a method for treating damage to the CNS by grafting donor cells into the CNS that have been modified to produce molecules such as neurotrophins.
The use of transplanted neural cells is also of limited clinical value: although axons will be able to grow into the transplanted tissue, they will not be able to grow out of the transplanted tissue back into the CNS due to inhibitory matter in the CNS.
This review of current methods of treating spinal cord injuries indicates that a need remains for a means of promoting regrowth, repair, and regeneration of neurons in the mammalian CNS in both the acute and chronic situations.
Myelin
It has been suggested that the failure of CNS axons to regenerate after injury is associated with the presence of myelin. The myelin sheath wrapping an axon is composed of compacted plasma membranes of Schwann cells and oligodendrocytes. Although its composition resembles that of any other plasma membrane in that it contains lipids, proteins, and water, the relative proportions and dispositions of these components are unique to myelin. Myelin in the CNS is produced by oligodendrocytes and is characterized by the expression of myelin basic protein (MBP). MBP is only associated with myelin and is one of the first proteins expressed at the onset of myelination of CNS axonal fibers. Galactocerebroside (GalC) is the major sphingolipid produced by oligodendrocytes. GalC comprises approximately 15 percent of the total lipid in human myelin and is highly conserved across species. Although GalC is expressed on the surface of oliogodendrocyte cell bodies, it is expressed in greater concentration on the surface of myelin membranes (Ranscht et al., (1982)
Proc. Natl. Acad. Sci. USA
79:2709-2713).
There is growing evidence that the presence of CNS myelin can retard or inhibit the regenerative growth of some severed CNS axons (Schwab and Bartoldi (1996)
Physiol. Rev
. 76:319-370), including a number of examples from widespread vertebrate families (Schwegler et al., (1995)
J. Neurosci
. 15:2756-2767; Steeves et al., (1994)
Prog. Brain Res
. 103:243-262). Both the lower vertebrate CNS (e.g. lamprey) and the developing CNS of higher vertebrates (e.g. birds and mammals) exhibit substantial axonal regeneration after injury (Davis and McClellan (1994)
J. Comp. Neurol
. 344:65-82; Hasan et al., (1993)
J. Neurosci
. 13:492-507; Hasan et al., (1991)
Restor. Neurol. Neurosci
. 2:137-154; Iwashita et al., (1994)
Nature
367:167-170; Saunders et al., (1992)
Proc. R. Soc. Lond. B. Biol
. 250:171-180; Treheme et al., (1992)
Proc. Natl. Acad. Sci. USA
89:431-434; Varga et al., (1995)
Eur. J. Neurosci
. 7:2119-2129). The common phenotype for all these positive examples of regeneration is either a CNS that lacks compact myelin (lamprey) or incomplete myelin development (embryonic chick, neonatal opossum and rat) at the time of injury. The developmental appearance of myelin temporally correlates with the loss of regeneration by injured CNS axons. In addition, the robust growth of transplanted fetal neurons in the adult CNS (Bregman et al., (1993)
Exp. Neurol
. 123:3-16; Li and Raisman (1993)
Brain Res
. 629:115-127; Yakovleff et al., (1995)
Exp. Brain Res
. 106:69-78) may be partially attributed to either a lack of receptors for myelin inhibitors at that stage of their differentiation and/or an ability to override any inhibitory signals from myelin. Specific molecules associated with myelin have been identified as putative mediators of this inhibitory activity, including myelin-associated glycoprotein (MAG) (McKerracher et al., (1994)
Neuron
. 13:805-811; Mukhopadhyay et al., (1994)
Neuron
. 13:757-767) and NI35/250, an as yet unidentified myelin-derived protein (Bandtlow and Schwab (1991)
Soc. Neurosc
Dyer Jason K.
Keirstead Hans S.
Steeves John D.
Allen Marianne P.
Fish & Richardson P.C.
University of British Columbia
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