Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
2000-08-18
2004-06-15
Falk, Anne-Marie (Department: 1636)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S093100, C514S012200
Reexamination Certificate
active
06749850
ABSTRACT:
1. BACKGROUND
The central nervous system (CNS) is particularly vulnerable to insults that result in cell death or damage in part because cells of the CNS have a limited capacity for repair. As a result, disorders of the CNS often result in debilitating and largely irreversible degradation of a patient's cognitive and sensorimotor functions. Conditions that result in nerve cell death and damage range from degenerative disorders, such as Alzheimer's disease, to ischemic episodes, such as stroke, to trauma.
Injury to the central nervous system (CNS) is an important cause of death and disability worldwide. For example, stroke is the third leading cause of death and disability in the U.S., with an estimated incidence of 700,000 cases annually (Furie et al. (1998) “Cerebrovascular Disease” in
The Atlas of Clinical Neurology
, R. N. Rosenberg, Ed. Current Medicine: Philadelphia). Two-thirds of stroke patients survive the first year following stroke, for an average of seven years, leading to more than 4.8 million stroke survivors currently in the U.S. Stroke costs the U.S. economy in excess of $30 billion per year in terms of medical costs and lost wages.
After several hours, little can be done to prevent the direct damage to the CNS caused by CNS disorders. For example, stroke treatments must typically be administered within six hours of onset. Depending on where the injury occurs in the brain, patients may be paralyzed on one side, may lose the ability to speak or see, and may have difficulty walking, among other symptoms. Gradual recovery of these functions is common, although recovery may be incomplete, and depends on the size and location of injury, among other factors.
Since damaged brain tissue does not regenerate, recovery must come from the remaining intact brain, which reorganizes itself, or rewires, in order to compensate for some of the function lost by the damage. Indeed, studies in animals and humans provide ample evidence of such reorganization of brain function following stroke. In particular, remaining neurons in both the damaged hemisphere and in the opposite intact hemisphere grow new processes (both axons and dendrites) and form new connections (synapses), which most likely contribute to recovery (Kawamata et al. (1997)
Proc. Natl. Acad. Sci. USA
, 94: 8179-8184; Jones et al. (1994)
J. Neurosci
., 14: 2140-2152; Stroemer et al. (1998)
Stroke
, 29: 2381-2395; Cramer et al. (1997)
Stroke
, 28: 2518-2527).
As an example, stroke treatment has focused on limiting the extent of damage within the first few hours. Stroke is generally due to a blockage of an artery leading to the brain, resulting in the death of brain cells supplied by that artery. Current treatments for stroke have centered on treatments to prevent arterial blockages (control of blood pressure, lipids, heart disease, etc.), and treatments to prevent brain damage once the blockage has occurred. These latter treatments include “thrombolytic agents” (“clot busters” such as tPA) to break up arterial clots, and “neuroprotective agents,” designed to protect brain tissue at risk for stroke. Such thrombolytic and neuroprotective agents must be administered within hours after the onset of stroke in order to be effective.
Currently there are only a few available methods of promoting recovery in patients after cell death and injury has already occurred. Methods of treating stroke after the initial phase of damage are mechanistically different from methods used in the first few hours. Treatments to promote recovery typically focus on encouraging neuronal growth and rewiring.
Direct application of neurotrophic growth factors to the brain can enhance spontaneous functional recovery occurring in animal models of stroke (Kawamata et al. (1997)
Proc. Natl. Acad. Sci. USA
, 94: 8179-8184; Kawamata et al. (1996)
J. Cereb. Blood Flow Metab
., 16: 542-547; Kawamata et al. (1999)
Exp. Neurol
. 158: 89-96; Alps et al., U.S. Pat. No. 5,733,871, Fisher et al. (1995)
J. Cereb. Blood Flow Metab
., 15: 953-959; Jiang et al. (1996)
J. Neurol. Sci.,
139: 173-179). For example, basic fibroblast growth factor (bFGF) is a protein that supports survival and axonal outgrowth from neurons. When bFGF is administered starting a day or more after stroke, animals recover more quickly and to a greater extent on tests of sensorimotor function of the impaired limbs (opposite to the side of the stroke). This recovery is not due to a decrease in magnitude of the original brain damage. Instead, data suggests that this enhancement of recovery may be due to enhancement of new neuronal sprouting and synapse formation in the intact remaining brain tissue. Such remodeling appears to occur in both the damaged and undamaged hemispheres. Other mechanisms of recovery may include stimulation of endogenous neural stem cells within the brain that then differentiate into neurons, replacing to some extent neurons lost by stroke.
Another potential approach to a treatment for stroke recovery includes the use of neural stem cells. These are pluripotential cells already present in the developing and mature mammalian brain that, given the appropriate stimulation, can differentiate into brain neurons and/or glial cells. Several investigators have been successful in separating and cloning out such neural stem cell lines from both the murine and human brain (Snyder et al. (1997)
Proc. Natl. Acad. Sci. USA
, 94: 11663-11668; Gage et al. (1995)
Proc. Natl. Acad. Sci. USA
, 92: 11879-11883; Kuhn et al. (1997)
J. Neurosci
., 17: 5820-5829; McKay et al., U.S. Pat. No. 5,270,191; Johe, K., U.S. Pat. No. 5,753,506; Carpenter, M., U.S. Pat. No. 5,968,829; Weiss et al., U.S. Pat. No. 5,750,376). When such stem cells are reintroduced into the developing or mature brain, they can divide, migrate, grow processes, and assume neural phenotypes, including the expression of neurotrarsmitters and growth factors normally elaborated by neurons. Thus, use of neural stem cells may be advantageous for stroke recovery in at least two ways: (1) by the stem cells partially repopulating dead areas and re- establishing neural connections lost by stroke, and (2) by secretion of important neurotrarsmitters and growth factors required by the brain to rewire after stroke. Efforts to promote recovery from brain injury in animals using neural stem cells have been described (Park et al. (1999)
J. Neurotrauma
16: 675-687; Park et al. (1995)
Soc. Neurosci. Abs
. 21: 2027; Stroemer et al. (1999)
Soc. Neuroscience Abs
. 25:1310). Efforts using a line of teratocarcinoma-derived cells have also been described in animals (Borlongan et al. (1993)
Int. J. Devl. Neuroscience
11: 555-568) and humans (Kokaia et al. (1998)
Eur. J. Neurosci
., 10: 2026-36).
Methods currently available for promoting recovery from CNS damage allow only partial recovery of neurological functions. In patients suffering from debilitating neurological deficits, incremental improvements in function may have a significant effect on quality of life. Given the large number of affected patients and the limitations of current methods, there is an urgent need for additional and improved methods to promote recovery from damage to the nervous system. The modes of treatment presented herein promote a greater degree of recovery from CNS damage than is currently available with other known treatment methods.
2. SUMMARY OF THE INVENTION
One aspect of the present application relates to methods for improving a subject's recovery from CNS injury or damage. In one aspect, the invention comprises administering to a subject cells, preferably stem cells, and a neural stimulant in sufficient amounts to improve the subject's sensorimotor or cognitive abilities, e.g., improved limb movement and control or improved speech capability.
In another aspect, the invention provides kits for the treatment of CNS damage. In certain embodiments, kits of the invention comprise stem cells and a neural stimulant. In other embodiments, the kits of the invention comprise a neural stimulant and a device for obtaining a stem cell-containing s
Finkelstein Seth P.
Snyder Evan Y.
Falk Anne-Marie
Foley & Hoag LLP
Sullivan Daniel M.
The General Hospital Corporation
LandOfFree
Methods, compositions and kits for promoting recovery from... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Methods, compositions and kits for promoting recovery from..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods, compositions and kits for promoting recovery from... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3346766