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

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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.

Original languageEnglish
Article number21301
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - Feb 16 2016

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Morpholinos
Amyotrophic Lateral Sclerosis
Phenotype
Motor Neurons
Induced Pluripotent Stem Cells
Mutation
Survival
Mutant Proteins
Neurodegenerative Diseases
Axons
Disease Progression
Therapeutics
Superoxide Dismutase-1
Clinical Trials
Amyotrophic lateral sclerosis 1

ASJC Scopus subject areas

  • General

Cite this

Morpholino-mediated SOD1 reduction ameliorates an amyotrophic lateral sclerosis disease phenotype. / Nizzardo, M.; Simone, C.; Rizzo, F.; Ulzi, G.; Ramirez, A.; Rizzuti, M.; Bordoni, A.; Bucchia, M.; Gatti, S.; Bresolin, N.; Comi, G. P.; Corti, S.

In: Scientific Reports, Vol. 6, 21301, 16.02.2016.

Research output: Contribution to journalArticle

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AU - Rizzuti, M.

AU - Bordoni, A.

AU - Bucchia, M.

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AU - Comi, G. P.

AU - Corti, S.

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