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) sustains the viability and phenotypic expression of a variety of neuronal populations in the central nervous system. Cranial and spinal motor neurons are particularly sensitive to the trophic effects of CNTF, and clinical trials are underway testing the potential therapeutic value of this trophic factor in patients with amyotrophic lateral sclerosis. Yet, the distribution of the alpha subunit of the receptor for ciliary neurotrophic factor (CNTFR alpha), which is essential for the trophic effects of CNTF to occur, is unknown in any primate species. Towards this end, the present study used a polyclonal antibody directed against CNTFR alpha to evaluate the distribution of CNTFR alpha-immunoreactive (-ir) cells within the brain and spinal cord of Cebus apella monkeys. CNTFR alpha-ir was found exclusively within neurons. In the anterior horn of the spinal cord, virtually all motor neurons were darkly immunoreactive for CNTFR alpha. A similar pattern of CNTFR alpha-ir was seen within all cranial motor nuclei with general somatic efferent function (III, IV, motor V, VI, VII, and XII cranial nerves). CNTFR alpha-ir was also seen in other regions involved with motor function including the Purkinje cells of the cerebellum, the substantia nigra pars compacta, red nucleus, dorsal motor nucleus of X cranial nerve, and giant neurons of sensory motor neocortex. A few CNTFR alpha-ir neurons were seen within the globus pallidus with concomitant terminal-like staining within the subthalamic nucleus. Autonomic regions such as the mesencephalic nucleus of the trigeminal nerve and the interomedial lateral cell column of the thoracic spinal cord also contained CNTFR alpha-ir neurons. Finally, the hippocampus displayed dense CNTFR alpha-ir within the pyramidal cell layer of the hippocampal formation and the granule cell layer of the dentate gyrus. The dense expression of this CNTFR alpha protein within regions subserving motor, autonomic, and sensory functions suggests that CNTFR alpha supports many central nervous system regions with diverse functions.
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PMID:Ciliary neurotrophic factor receptor alpha-immunoreactivity in the monkey central nervous system. 898 52

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) is a 10-item functional inventory which was devised for use in therapeutic trials in ALS. Each item is rated on a 0-4 scale by the patient and/or caregiver, yielding a maximum score of 40 points. The ALSFRS assesses patients' levels of self-sufficiency in areas of feeding, grooming, ambulation and communication. Rotated factor analysis of the ALSFRS found that the rating items group logically and consistently into four categories. The ALSFRS has been validated both cross-sectionally and longitudinally against muscle strength testing, the Schwab and England ADL rating scale, the Clinical Global Impression of Change (CGIC) scale, and independent assessments of patient's functional status. In this report, we use the data provided by the placebo patients who participated in the ALS CNTF Treatment Study (ACTS) to demonstrate the robustness, test-retest reliability and consistency of the ALSFRS as employed in a large, multicenter clinical trial.
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PMID:Performance of the Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) in multicenter clinical trials. 941 47

It has been shown that abnormalities in axonal transport occur in several mouse models with motoneuron degeneration and also in the human disease amyotrophic lateral sclerosis. In this report, we have examined the potential of neurotrophic factors to act on axonal transport properties in a mouse mutant, progressive motor neuronopathy (pmn). This mouse mutant has been characterized as a "dying-back" motoneuronopathy, with a loss of motoneuron cell bodies and motor fibers. Retrograde transport to the spinal cord motoneurons was determined using fluorescent tracers either injected into the gastrocnemius muscle or applied directly onto the cut sciatic nerve. Because the rate of retrograde labeling was significantly reduced in the pmn, we examined the potential of neurotrophic factors to compensate for the impairment. Ciliary neurotrophic factor (CNTF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) but not glial-derived neurotrophic factor (GDNF) or nerve growth factor (NGF) were capable of significantly improving the rate of labeling. The differential effects of these factors agree with previous studies showing that molecules that promote cell survival do not necessarily compensate for axonal deficiency. Because impairment of axonal properties appears as an early event in motoneuron pathology, our results may have important clinical implications in the treatment of motoneuron diseases.
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PMID:Differential effects of neurotrophic factors on motoneuron retrograde labeling in a murine model of motoneuron disease. 943 33

We analyzed data from the 245-patient placebo group of the ALS CNTF Treatment Study Group study, a large, prospective, multicenter study of recombinant human ciliary neurotrophic factor to determine prognostic factors for length of survival in ALS. Variables examined included baseline demographic characteristics, indices of disease severity, pulmonary function, and clinical laboratory tests. Shorter survival was associated with greater age, lower percent-predicted forced vital capacity (FVC%), and lower serum chloride at study entry. A shorter interval from symptom onset to diagnosis of ALS and greater weight loss in the 2 months before study entry also predicted shortened survival times. The rate of muscle strength loss before study entry did not predict risk of mortality. Serum chloride, reflecting the degree of respiratory acidosis, was identified for the first time as being correlated with prognosis in ALS. The relationship between a patient's FVC% and the probability of survival is described.
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PMID:Prognostic indicators of survival in ALS. ALS CNTF Treatment Study Group. 944 59

Glial cell line-derived neurotrophic factor (GDNF) is the most potent known survival factor for substantia nigra neurons, which degenerate in Parkinson's disease, for spinal motoneurons, which die in Lou Gehrig's disease (ALS), and for Purkinje neurons, the critical outflow cells of the cerebellum. Moreover, targeted deletion of the GDNF gene results in renal dysgenesis and abnormal development of the enteric nervous system. GDNF mRNA is expressed in a complex temporospatial pattern in the central nervous system and the periphery, consistent with these observations. To begin elucidating mechanisms regulating the pattern of expression of GDNF, we have cloned the human gene, and characterized the promoter. The promoter is highly GC rich, and lacks canonical CCAT-box and TATA-box motifs. It contains more than 12 binding sites for known transcription factors. These cis-elements have the potential to interact with factors regulating constitutive expression (Sp1) and developmental expression (bHLH). Moreover, the promoter contains sites for binding transcription factors which respond to environmental signals, including CREB, AP2, Zif/268, NFkB, and MRE-BP. Combinatorial actions of these transcription factors may account for the extraordinarily complex expression patterns of the GDNF gene. Importantly, we demonstrate that the hGDNF gene utilizes a promoter distinct from that identified in the rodent GDNF gene, a finding with ramifications for Parkinson's disease and ALS research.
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PMID:Novel structure of the human GDNF gene. 972 3

Several neurotrophic factors (CNTF, BDNF, IGF-1) have been suggested for the treatment of motor neuron diseases. In ALS patients, however, the repeated subcutaneous injection of these factors as recombinant proteins is complicated by their toxicity or poor bioavailability. We have constructed an adenovirus vector coding for neurotrophin-3 (AdNT-3) allowing for stable and/or targeted delivery of NT-3 to motoneurons. The intramuscular administration of this vector was tested in the mouse mutant pmn (progressive motor neuronopathy). AdNT-3-treated pmn mice showed prolonged lifespan, improved neuromuscular function, reduced motor axonal degeneration and efficient reinnervation of muscle fibres. NT-3 protein and also adenovirus vectors, when injected into muscle, can be transported by motoneurons via retrograde axonal transport to their cell bodies in the spinal cord. Using ELISA and RT-PCR analyses in muscle, spinal cord and serum of AdNT-3-treated pmn mice, we have investigated the contribution of these processes to the observed therapeutic effects. Our results suggest that most if not all therapeutic benefit was due to the continuous systemic liberation of adenoviral NT-3. Therefore, viral gene therapy vectors auch as adenoviruses, AAVs, lentiviruses and new types of gene transfer not based on viral vectors that allow for efficient in vivo liberation of neurotrophic factors have potential for the future treatment of human motor neuron diseases.
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PMID:Adenovirus-mediated transfer of the neurotrophin-3 gene into skeletal muscle of pmn mice: therapeutic effects and mechanisms of action. 985 58

Growth factors are theoretically promising agents for ALS therapy, but have been disappointing in subcutaneous delivery due to either toxicity or lack of major efficacy. Leukaemia inhibitory factor (LIF), was named after its effect on haemopoietic cells, and belongs to a group of cytokines which includes CNTF, IL-6, CT-1, OM and IL-11. All group members use the gp130 signal transducing subunit for intracellular signalling, but show differences in biological effect. In vitro and in vivo studies on axotomy and nerve crush models demonstrate a powerful effect of LIF in the survival of both motor and sensory neurones, while reducing denervation induced muscle atrophy. Its effects in muscle also include stimulating myoblast proliferation in vitro, and up-regulation after muscle injury. LIF will also stimulate muscle regeneration in vivo when applied exogenously after injury. In published studies of both axotomy induced neuronal death and in the Wobbler mouse models LIF is active at doses of 10 microg/kg delivered systemically, well below the expected maximum tolerated dose suggested by primate safety studies. LIF is expressed in low levels by spinal cord neurones with significant up-regulation when the neurones are damaged by BOAA toxin, an excitatory amino acid associated with a form of ALS. This augments other evidence suggesting LIF is a trauma factor playing a role in the injury response of adult neuronal tissue, and may be more effective than related growth factors. Taken together, the data suggests LIF is a physiologically relevant trophic factor with implications in clinical medicine as a therapy for ALS, and a human recombinant form (AM424), entered human clinical trials during 1998.
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PMID:LIF (AM424), a promising growth factor for the treatment of ALS. 985 59

Ciliary neurotrophic factor (CNTF) has demonstrated therapeutic effects in several mouse mutants with motoneuronal degeneration. However, the poor bioavailability and toxic side effects of recombinant CNTF protein have complicated its use in patients with amyotrophic lateral sclerosis. CNTF gene transfer strategies were developed but faced the question of whether CNTF should be delivered to motoneuron cell bodies or to their axons or muscle targets. To address this issue, we have used an adenoviral vector (AdCNTF) coding for a secretable form of CNTF and compared different routes of its administration in the mouse mutant progressive motor neuronopathy (pmn). Intramuscular, intravenous, and intracerebroventricular injections of AdCNTF or the control vector AdlacZ resulted in transgene expression in skeletal muscle fibers, hepatocytes, and ependymal cells, respectively, as determined by histochemistry and reverse transcription-polymerase chain reaction. AdCNTF intramuscularly treated and intravenously treated pmn mice showed a 25% increase in mean life span and a reduced degeneration of phrenic myelinated nerve fibers, which correlated with elevated CNTF serum bioactivities. In contrast, intracerebroventricular AdCNTF administration did not affect the mean life span or motor axonal degeneration of pmn mice. The differential efficacy of peripheral and central CNTF vector administrations might be of interest for future studies in human motor neuron diseases.
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PMID:Therapeutic benefit of ciliary neurotrophic factor in progressive motor neuronopathy depends on the route of delivery. 1007 43

Motoneurons need muscle-derived neurotrophic substances for their survival during the initial phase of their development, but after maturation they lose this requirement and can survive after axotomy. This suggests that some neurotrophic substances other than target-derived ones control the survival of motoneurons in adults. Because spinal motoneurons express fibroblast growth factor-9 (FGF-9) messenger RNA, we hypothesized that FGF-9 might be an autocrine or paracrine survival factor for motoneurons. FGF-9 promoted the survival of motoneurons and upregulated the choline acetyl-transferase (ChAT) activity in the dissociated cultures of ventral half of rat E13 spinal cord. Externally added FGF-9 was more effective in low density cultures, and polyclonal blocking antibody against FGF-9 significantly lowered the ChAT activity. Our results support an autocrine or paracrine role for FGF-9 in mediating the survival of spinal motoneurons. Non-target-derived neurotrophic substances for motoneurons including FGF-9 should be important in the pathogenesis of motor neuron disorders in the adults, especially amyotrophic lateral sclerosis.
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PMID:FGF-9 is an autocrine/paracrine neurotrophic substance for spinal motoneurons. 1045 63

Ciliary neurotrophic factor (CNTF), a potent survival factor in spinal motoneurons of embryonic chick and rat, is currently being investigated in humans as a treatment for amyotrophic lateral sclerosis (ALS). However, its physiological and pathological activities in ALS remain unclear. We measured CNTF contents in the cervical enlargement of the spinal cord from 9 ALS patients and 12 age-matched control subjects using a sensitive enzyme-linked immunoassay. CNTF genotypes were determined by the polymerase chain reaction-restriction fragment length polymorphism method. In control subjects, there were 8 homozygotes and 4 heterozygotes, while in ALS patients there were 6 and 3, respectively. In both homozygotes and heterozygotes, CNTF expression in the spinal cord from ALS patients tended to decrease compared to control subjects. In homozygotes, the decrease was significant (p < 0.05). Concerning the regional concentrations of CNTF, in homozygotes, CNTF contents in the lateral corticospinal tract were markedly lower (p < 0.001) in ALS patients than in controls. The decrease in CNTF expression in the lateral corticospinal tract of the spinal cord from ALS patients may be a feature of ALS and could be related to motor neuron loss.
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PMID:Decrease in the ciliary neurotrophic factor of the spinal cord in amyotrophic lateral sclerosis. 1052 43


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