Neurotoxicity due to the accumulation of mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS); these mutations result in progressive motor neuron death through one or more acquired toxicities. Interestingly, SOD1 is not only responsible for fALS but may also play a significant role in sporadic ALS; therefore, SOD1 represents a promising therapeutic target. Here, we report slowed disease progression, improved neuromuscular function, and increased survival in an in vivo ALS model following therapeutic delivery of morpholino oligonucleotides (MOs) designed to reduce the synthesis of human SOD1. Neuropathological analysis demonstrated increased motor neuron and axon numbers and a remarkable reduction in astrogliosis and microgliosis. To test this strategy in a human model, we treated human fALS induced pluripotent stem cell (iPSC)-derived motor neurons with MOs; these cells exhibited increased survival and reduced expression of apoptotic markers. Our data demonstrated the efficacy of MO-mediated therapy in mouse and human ALS models, setting the stage for human clinical trials.

Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral sclerosis disease phenotype / M. Nizzardo, C. Simone, F. Rizzo, G. Ulzi, A. Ramirez, M. Rizzuti, A. Bordoni, M. Bucchia, S. Gatti, N. Bresolin, G.P. Comi, S. Corti. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016), pp. 21301.1-21301.13. [10.1038/srep21301]

Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral sclerosis disease phenotype

M. Nizzardo;C. Simone;F. Rizzo;G. Ulzi;A. Ramirez;A. Bordoni;M. Bucchia;N. Bresolin;G.P. Comi;S. Corti
2016

Abstract

Neurotoxicity due to the accumulation of mutant proteins is thought to drive pathogenesis in neurodegenerative diseases. Mutations in superoxide dismutase 1 (SOD1) are linked to familial amyotrophic lateral sclerosis (fALS); these mutations result in progressive motor neuron death through one or more acquired toxicities. Interestingly, SOD1 is not only responsible for fALS but may also play a significant role in sporadic ALS; therefore, SOD1 represents a promising therapeutic target. Here, we report slowed disease progression, improved neuromuscular function, and increased survival in an in vivo ALS model following therapeutic delivery of morpholino oligonucleotides (MOs) designed to reduce the synthesis of human SOD1. Neuropathological analysis demonstrated increased motor neuron and axon numbers and a remarkable reduction in astrogliosis and microgliosis. To test this strategy in a human model, we treated human fALS induced pluripotent stem cell (iPSC)-derived motor neurons with MOs; these cells exhibited increased survival and reduced expression of apoptotic markers. Our data demonstrated the efficacy of MO-mediated therapy in mouse and human ALS models, setting the stage for human clinical trials.
spinal muscular-atrophy; ALS-linked SOD1; motor-neurons; mutant SOD1; mouse model; antisense oligonucleotide; extends survival; misfolded SOD1; inherited ALS; cell-death
Settore MED/26 - Neurologia
Settore MED/03 - Genetica Medica
Settore BIO/18 - Genetica
Settore BIO/05 - Zoologia
Settore MED/50 - Scienze Tecniche Mediche Applicate
SCIENTIFIC REPORTS
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/398257
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