Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ciliary neurotrophic factor (CNTF) has recently generated great interest due to its potential as a therapeutic agent for the treatment of human neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Because the systemic half-life of CNTF is only in the order of a few minutes, continuous delivery of this trophic factor could be attractive or even necessary in the therapy of these diseases. One promising technique involves the polymer encapsulation of cells which have been genetically modified to secrete neurotrophic factors. The polymer capsules can be implanted into animals and effect the slow release of the protein for several months. The encapsulation technique immuno-isolates the foreign cells from host immune cells and at the same time prevents tumour formation by the transplanted cells. In this study, we have used progressive motoneuronopathy (pmn) mice to determine the extent to which encapsulated cell lines secreting CNTF could alter the course of the disease. pmn/pmn homozygotes present severe loss of myelinated motor fibres and a significant reduction of facial motoneuron cell bodies. The mice develop weakness of the hindlimbs and die during the sixth week after birth. We found that CNTF delayed the disease progression by increasing the survival time by 40% and by improving motor function as assessed by three behavioural tests. Moreover, histological counts of the phrenic nerve myelinated axons and facial nucleus motoneurons indicated a significant reduction of motoneuron loss. These results suggest that polymer-encapsulated cells releasing neurotrophic factors may provide a potential delivery system for treating neurodegenerative diseases such as ALS.
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PMID:Polymer encapsulated cell lines genetically engineered to release ciliary neurotrophic factor can slow down progressive motor neuronopathy in the mouse. 758 5

Ciliary neurotrophic factor (CNTF) rescues motor neurons in animal models of injury and neurodegeneration, and disruption of the mouse CNTF gene results in motor neuron degeneration in mature adults. Glial cells increase nerve growth factor (NGF) expression in neuropathological conditions, and the sensory system can be affected in the amyotrophic lateral sclerosis (ALS) type of motor neuronic disease. We therefore studied CNTF and NGF levels in post mortem spinal cord and cerebral cortex from patients with ALS and matched controls. We report a marked decrease of CNTF in the ventral horn of spinal cord in ALS, with no change in cerebral motor cortex. In contrast, NGF levels were decreased in ALS cerebral motor cortex, where the corticospinal tract originates, but increased in the lateral column of spinal cord, which includes the region of corticospinal tract degeneration in ALS. Both CNTF and NGF levels were decreased in ALS dorsal spinal cord.
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PMID:Regional changes of ciliary neurotrophic factor and nerve growth factor levels in post mortem spinal cord and cerebral cortex from patients with motor disease. 758 15

Ciliary neurotrophic factor (CNTF) is known to rescue motor neurones in animal models of injury and neurodegeneration and we have recently described regional changes of CNTF protein levels in spinal cord from patients with sporadic motor neurone disease of the amyotrophic lateral sclerosis (ALS) type. However, information is lacking about the CNTF receptor in this condition. We have therefore studied mRNA levels for the alpha subunit of the CNTF receptor (CNTFR alpha) and for CNTF itself in postmortem spinal cord and cerebral cortex in patients with sporadic ALS and matched controls. We report that in the spinal cord of ALS patients there is a marked increase in the hybridisation signal for CNTFR alpha subunit mRNA overlying motor neurones. In contrast, very little mRNA for CNTFR alpha subunit was found in the motor cortex and no differences were seen between ALS and controls. We were unable to detect any hybridisation signal for CNTF mRNA. Our findings provide evidence for regional differences in CNTF receptor expression in upper- and lower-motor neurones in ALS.
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PMID:Ciliary neurotrophic factor receptor expression in spinal cord and motor cortex in amyotrophic lateral sclerosis. 759 99

ALS is associated with the P2 blood group phenotype. Molecular evidence now shows the gene encoding this antigen to be on the long arm of human chromosome 22 near the newly discovered gene for heavy neurofilament (NF-H). Since an ALS-type condition can be generated in transgenic mice expressing the human NF-H gene, and since the gene for the CNTF-related cytokine leukemia inhibitory factor (LIF) is located adjacent to this gene, it is hypothesized that a defect on the chromosome 22 band region q12 is involved in the pathogenesis of sporadic ALS.
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PMID:Sporadic ALS and chromosome 22: evidence for a possible neurofilament gene defect. 773 42

The recent molecular cloning of BDNF and CNTF based on traditional protein purification and protein sequencing and the identification and cloning of NT-3 and NT-4 by homology cloning strategies has led to a tremendous flurry of interest in the biology of these proteins and initiation of studies to assess their potential utility in neurological disorders ranging through degenerative disease, stroke and ischemia, trauma and peripheral neuropathies. Tissue culture studies have been very useful in identifying neuronal specificities of the neurotrophins and CNTF and in combination with localization studies of these growth factors and their receptors have provided the basis for in vivo studies. Initial animal studies with BDNF indicate efficacy of BDNF in models of Alzheimer's and Parkinson's disease and small fiber sensory neuropathy. Studies with CNTF have similarly progressed from in vitro findings, especially the discovery that CNTF is a growth factor for motor neurons, to in vivo findings where CNTF has been shown to be effective in slowing symptoms of motor neuron dysfunction in three genetic models. Based on these positive animal data, CNTF is currently in clinical trials for the potential treatment of motor neuron disease or amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease.
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PMID:Neurotrophic growth factors and neurodegenerative diseases: therapeutic potential of the neurotrophins and ciliary neurotrophic factor. 783 3

Motor neurone disease, or amyotrophic lateral sclerosis, is a serious progressive neurological disorder, characterized by loss of UMN and LMN. Pathological features include characteristic intracytoplasmic MN inclusion bodies and appearances on ubiquitin staining. The aetiopathogenesis of the disease remains unknown and there is, to date, no effective treatment. Several abnormalities have been demonstrated in neurotransmitter, neuropeptide and gene expression studies. Abnormalities in glutamate metabolism have led to the excitotoxin hypothesis of MN destruction. Other theories include deficits in MN trophic factors, trans-synaptic degeneration, impaired ability to detoxify putative toxic agents and impaired DNA/RNA metabolism. The existence of familial forms, some of which show linkage to markers in chromosome 21, allows a genetic approach to the mechanisms of disease. Recent studies suggest that mutations in the Cu/Zn SOD gene may be important in some of the familial forms. The atypical forms seen in the Western Pacific have stimulated a search for environmental agents. Agents undergoing therapeutic trials at present include CNTF, IGF1 glutamate antagonists, branched-chain amino acids and TRH analogue.
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PMID:Motor neurone disease. 792 18

We examined 101 sera from 32 adult sporadic amyotrophic lateral sclerosis (ALS) patients, including nine with positive enzyme-linked immunosorbent assay (ELISA) serum antibodies against human spuma retrovirus (HSRV) [human foamy virus (HFV)] envelope (env) and/or capsid (gag) proteins, for peptide seroreactivity. Synthetic peptides 10 to 14 amino acids in length were selected from HSRV (3), maedi-visna virus (1), human nerve growth factor-beta (1), and human amyloid-beta sequences (1). Eighteen of 101 ALS sera compared with six of 144 control sera reacted to any of the sequences (p < 0.01) (i.e., 8/32 ALS patients and 2/93 control patients bound to a synthetic peptide, p < 0.01). Peptide VLA- [NGF beta(1-14)] was reproducibly recognized by one of the 93 neurologic controls, and one of the 32 ALS patients reproducibly reacted to synthetic peptides [EET-, HSRVenv/NGF beta(55-61)] and [GSN-, beta-amyloid(25-35)] simultaneously. This amyloid-A(25-35) peptide corresponds to the neurotoxic and neurotrophic tachykinin homology sequence described by Yanker. Only ALS patients (no controls) reacted with the visna/CNTF peptide SMC- and HSRVbcl-1/amyloid(740-751) peptide EGP-. Testing a total of 245 sera from 125 patients, three reproducible reactivities (two ALS, one OND) were observed both with and without glutaraldehyde linkage. Of the four peptides recognized either by more than one serum from the same patient with ALS or by sera from ALS patients only (EET-, GSN-, SMC-, EGP-), two share a circumscript homology with maedi-visna virus envelope glycoprotein (Table 1).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Retroviral synthetic peptide serum antibodies in human sporadic amyotrophic lateral sclerosis. 800 25

Ciliary neurotrophic factor (CNTF) supports the survival of motoneurons in vitro and in vivo. Recombinant CNTF is an investigational drug for the treatment of amyotrophic lateral sclerosis. We determined the pharmacokinetics of radioiodinated CNTF after intravenous injection into rats. CNTF shows a biphasic clearance with an initial plasma half-life of 2.9 minutes and is removed from the circulation by the liver. No accumulation of radioactivity was detectable in nerve tissue or skeletal muscle after intravenous injection of 0.1 microgram and 0.5 microgram of CNTF. Radioactive degradation products accumulate in the skin. Liver cells express specific binding proteins for CNTF, and the incorporation and degradation of intravenously injected CNTF by the liver may occur after association of CNTF with the soluble CNTF receptor alpha in the circulation. Probably as a consequence of its binding to hepatocytes, CNTF induces acute-phase responses in liver. The short half-life and the inflammatory side effect may limit the clinical usefulness of systematically administered CNTF in the treatment of human motoneuron disorders.
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PMID:Ciliary neurotrophic factor: pharmacokinetics and acute-phase response in rat. 810 93

Ciliary neurotrophic factor (CNTF) has recently been found to be important for the survival of motor neurons and has shown activity in animal models of amyotrophic lateral sclerosis (ALS). CNTF therefore holds promise as a treatment for ALS, and it and its receptor (CNTFR) are candidates for a gene involved in familial ALS. The CNTFR gene was mapped to chromosome 9 by PCR on a panel of human/CHO somatic cell hybrids and localized to 9p13 by PCR on a panel of radiation hybrids.
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PMID:Localization of the gene for the ciliary neurotrophic factor receptor (CNTFR) to human chromosome 9. 824

The survival and functional maintenance of spinal motoneurones and of peripheral neurones, such as sensory, sympathetic and parasympathetic neurones, has been shown to depend on neurotrophic factors, both during the period of developmental cell death and in adulthood. A variety of such factors has been identified over recent years, among them factors of the NGF gene family, for example BDNF, NT-3, NT-4/5 and NT-6, and factors such as CNTF and LIF acting on neuronal target cells via receptor components shared with cytokines such as IL-6. In addition, pluripotent mitogens, such as IGF-I and IGF-II can support the survival of a variety of neuronal cell types, including spinal motoneurones both in cell culture and in vivo. The establishment of mice in which the genes for these factors and their receptors have been inactivated by homologous recombination has been a major step in the understanding of their physiological function. It is not clear so far whether or not similar gene defects in human are associated with any neurological disease. However, some of these factors have been demonstrated to be effective in animal models of neuropathy and motoneurone disorders, so that first clinical trials using these factors for symptomatic treatment of amyotrophic lateral sclerosis (ALS) and peripheral neuropathies have already been initiated.
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PMID:Molecular biology of neurotrophic factors. 859 25


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