Methods and compositions for the treatment of injury to the...

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Carbohydrate doai

Reexamination Certificate

Rate now

  [ 0.00 ] – not rated yet Voters 0   Comments 0

Details

C435S006120, C435S069100, C435S325000, C435S366000, C536S023100, C536S024500

Reexamination Certificate

active

06475998

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention provides methods and compositions for treating trauma to the central nervous system (CNS). The present invention also provides methods and compositions for facilitating neuronal transplant.
2. Description of Related Art
The ACHE gene encoding the acetylcholine hydrolyzing enzyme, acetylcholinesterase (ACHE, EC 3.1.1.7), is expressed in muscle, nerve, hematopoietic cells, embryonic tissue and germ cells. ACHE maps to chromosome 7q22 and encodes the primary enzyme, acetylcholinesterase (AChE, E.C. 3.1.1.7), which terminates neurotransmission at synapses and neuromuscular junctions (NMJ). The text
Human Cholinesterases and Anticholinesterases
by Soreq and Zakut (Academic Press, Inc., 1993) provides a summation of the biochemical and biological background as well as the molecular biology of human cholinesterase genes. In addition Soreq et al. 1990; Seidman, et al. 1995; and Grifman et al., 1997 provide summations of various aspects of acetylcholinesterase biology. The text and references in their entirety are incorporated herein by reference.
Three alternative AChE-encoding mRNAs have been described in mammals. The dominant brain and muscle AChE found in NMJs (AChE-T) is encoded by an mRNA carrying exon E1 and the invariant coding exons E2, E3, and E4 spliced to alternative exon E6 (FIGS.
4
-
5
). AChEmRNA bearing exons E1-4 and alternative exon ES encodes the glycolipid phosphatidylinositol (GPI)-linked form of AChE characteristic of vertebrate erythrocytes (AChE-H). An additional readthrough mRNA species retaining the intronic sequence I4 located immediately 3′ to exon E4 was reported in rodent bone marrow and erythroleukemic cells and in various tumor cells lines of human origin.
In addition to its classical role as the enzyme responsible for acetylcholine hydrolysis, an increasing number of studies are suggesting a non-classical role for AChE in neurogenesis [reviewed in Robertson and Yu, 1993; Layer, 1995]. This is based on observations of intense patterns of AChE activity occurring transiently in many developing neural structures before synaptogenesis, or in locations which have no cholinergic synapses. In the vertebrate retina, four AChE-positive subbands have been described in the IPL [Marc, 1986; Hutchins, 1987], only two of which correspond to ChAT-positive subbands [Millar et al., 1985]. The other two are apparently not associated with cholinergic transmission. One possible explanation for these non-cholinergic AChE subbands is that they are related to neurite guidance. Several studies have demonstrated non-catalytic functions of AChE in the regulation of neurite outgrowth from embryonic neurons [Layer et al., 1992; Layer et al., 1993; Small et al., 1995].
It is proposed that AChE, and other cholinesterase-like molecules, are involved in cell-cell recognition. AChE displays homology to nervous system adhesion proteins such as neurotactin [de la Escalera, 1990; Darboux et al., 1996], gliotactin [Auld et al., 1995], and neuroligin [Ichtchenko et al., 1995]. Moreover, certain isoforms of AChE may possess an HNK-1 epitope that is commonly found on cell adhesion proteins [Bon et al., 1987].
Closed head injury (CHI) is a major cause of mortality and morbidity among young adults and an important risk factor in non familial Alzheimer's disease [French et al., 1991; Gentleman et al., 1993; Mayeux et al., 1995]. Following head trauma, disruption of the blood-brain-barrier contributes to the development of vasogenic edema. In addition, release of autodestructive factors leads to cytotoxicity and acute as well as delayed neuromotor and cognitive impairments [Caprusi and Levine, 1992; Hamm et al., 1996; Gennarelli, 1997]. The early phase of post-injury responses also includes a burst of released acetylcholine [Gorman et al., 1989] and elevated levels of intracellular calcium [Siesjo, 1993] in the brain. Pre-injury administration of the muscarinic antagonist scopolamine facilitates recovery from brain injury [Hamm et al., 1993], suggesting that rapid suppression of the early immediate intense stimulation mediated by acetylcholine released cholinergic hyperexcitation, during the first few post-injury minutes post-injury is therapeutically advantageous. However, other methods are needed that intervene at biologically significant steps so that recovery is assured and long-term risk factors for neurodegenerative diseases are avoided.
Acute cholinergic stimulation itself promotes a rapid and prolonged elevated overproduction (overexpression) of AChE [Friedman et al., 1996]. These elevated levels of AChE will act to brake the immediate phase of cholinergic hyperactivation. However, protracted overexpression of AChE will excessively suppress cholinergic neurotransmission.
Apart from its catalytic role, accumulated evidence establishes non-catalytic, neurite growth-promoting activities for AChE [Layer and Willbold, 1995, Koenigsberger et al., 1997; Sternfeld et al., 1998]. This suggests that elevated AChE levels might also promote a secondary phase of dendritic hypertrophy that could be important for short-term recovery from head injury such as CHI. Yet, it has been recently observed that extended overexpression of neuronal AChE in brain and spinal cord of transgenic mice promotes reduced dendritic branching, loss of dendritic spines (i.e. less synapses), and delayed, neuromotor and cognitive deficits [Beeri et al., 1995, 1997; Andres et al., 1997]. Together, these observations therefore raised the possibility that acute cholinergic stimulation following head trauma promotes an upregulation of AChE biosynthesis that is beneficial in the short term, but which causes long-term perturbations in the normal dendritic reorganization that takes place in the adult brain [Flood and Coleman, 1990, Arendt et al., 1995]. If so, the increased risk of AD among survivors of severe head injuries could be viewed as a delayed consequence of too long an exposure to AChE following injury and can potentially create imbalanced neurite extension and impaired targeting due to the neurite guidance role of AChE as described herein above. It would therefore be useful following head injury and any other injury to the central nervous system (CNS) to insure that an excess of AChE does not interfere with recovery, i.e. that a balance of AChE levels and timing is maintained. This is particularly critical in those patients which are already compromised in that their neural AChE levels are elevated due to biological, genetic or environmental factors.
It has been recently demonstrated [Chen et al, 1997A] that treatment of CHI with a brain specific inhibitor of anticholinesterase catalytic activity had a positive effect on short term recovery. However exposure to AChE enzymatic inhibitors itself activates a feedback loop leading to elevated levels of mRNA for AChE (AChEmRNA) [Friedman et al., 1996] and therefore this treatment has a potential for long term overexpression of AChE and subsequent development of neurodegenerative disease.
As with any therapy an appropriate model is required, either in vivo, ex vivo or in vitro. Since mice do not naturally overexpress AChE, Applicants have generated a unique transgenic mouse model for Alzheimer's Disease to serve this purpose [Beeri et al., 1995]. These genetically engineered mice overproduce human AChE in cholinergic brain cells providing a model of overexpressed AChE. Applicants' transgenic mice display age-dependent deterioration in cognitive performance as initially measured by a standardized swimming test for spatial learning and memory and a social recognition test. Since the excess acetylcholinesterase in the brains of these mice is derived from human DNA, it is a model for any intervention directed against human acetylcholinesterase protein and/or gene. This animal system and br

LandOfFree

Say what you really think

Search LandOfFree.com for the USA inventors and patents. Rate them and share your experience with other people.

Rating

Methods and compositions for the treatment of injury to the... 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 and compositions for the treatment of injury to the..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Methods and compositions for the treatment of injury to the... will most certainly appreciate the feedback.

Rate now

     

Profile ID: LFUS-PAI-O-2961167

  Search
All data on this website is collected from public sources. Our data reflects the most accurate information available at the time of publication.