Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS.

A novel HGF/SF receptor (MET) agonist transiently delays the disease progression in an amyotrophic lateral sclerosis mouse model by promoting neuronal survival and dampening the immune dysregulation / Vallarola, A.; Tortarolo, M.; De Gioia, R.; Iamele, L.; de Jonge, H.; de Nola, G.; Bovio, E.; Pasetto, L.; Bonetto, V.; Freschi, M.; Bendotti, C.; Gherardi, E.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 21:22(2020), pp. 1-20. [10.3390/ijms21228542]

A novel HGF/SF receptor (MET) agonist transiently delays the disease progression in an amyotrophic lateral sclerosis mouse model by promoting neuronal survival and dampening the immune dysregulation

Vallarola A.;
2020

Abstract

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with no effective treatment. The Hepatocyte Growth Factor/Scatter Factor (HGF/SF), through its receptor MET, is one of the most potent survival-promoting factors for motor neurons (MN) and is known as a modulator of immune cell function. We recently developed a novel recombinant MET agonist optimized for therapy, designated K1K1. K1K1 was ten times more potent than HGF/SF in preventing MN loss in an in vitro model of ALS. Treatments with K1K1 delayed the onset of muscular impairment and reduced MN loss and skeletal muscle denervation of superoxide dismutase 1 G93A (SOD1G93A) mice. This effect was associated with increased levels of phospho-extracellular signal-related kinase (pERK) in the spinal cord and sciatic nerves and the activation of non-myelinating Schwann cells. Moreover, reduced activated microglia and astroglia, lower T cells infiltration and increased interleukin 4 (IL4) levels were found in the lumbar spinal cord of K1K1 treated mice. K1K1 treatment also prevented the infiltration of T cells in skeletal muscle of SOD1G93A mice. All these protective effects were lost on long-term treatment suggesting a mechanism of drug tolerance. These data provide a rational justification for further exploring the long-term loss of K1K1 efficacy in the perspective of providing a potential treatment for ALS.
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A novel HGF/SF receptor (MET) agonist transiently delays the disease progression in an amyotrophic lateral sclerosis mouse model by promoting neuronal survival and dampening the immune dysregulation / Vallarola, A.; Tortarolo, M.; De Gioia, R.; Iamele, L.; de Jonge, H.; de Nola, G.; Bovio, E.; Pasetto, L.; Bonetto, V.; Freschi, M.; Bendotti, C.; Gherardi, E.. - In: INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES. - ISSN 1661-6596. - 21:22(2020), pp. 1-20. [10.3390/ijms21228542]
Vallarola, A.; Tortarolo, M.; De Gioia, R.; Iamele, L.; de Jonge, H.; de Nola, G.; Bovio, E.; Pasetto, L.; Bonetto, V.; Freschi, M.; Bendotti, C.; Gherardi, E.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1226962
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