Antisense oligonucleotides Morpholino therapy rescues ALS pathological effects in human and murine ALS models15

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

 Molecular therapy with Antisense Oligonucleotides Morpholino can improve ALS pathology in two experimental models. This important result has been published in the scientific international journal Scientific Reports.

It is a study performed by Monica Nizzardo e Stefania Corti from

“Centro Dino Ferrari”,

University of Milan,

IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico.

In a study published online in Scientific Reports (Nature publishing group) researchers at “Centro Dino Ferrari”, University of Milan, IRCCS Fondazione Ca’ Granda, Ospedale Maggiore Policlinico reported the therapeutic efficacy of antisense oligonucleotides morpholino in two experimental models of Amyotrophic Lateral Sclerosis (ALS).

ALS is a fatal neurological disease characterized by the degeneration and loss of upper and lower motor neurons, which lead to paralysis and death within 3–5 years of diagnosis. The majority of cases of ALS have no clear genetic linkage and are referred to as sporadic, while 10% of cases are familial. Mutations in the gene encoding for Cu/Zn superoxide dismutase 1 (SOD1) are relatively frequent, accounting for 20% of sporadic ALS and causing a toxic accumulation of the SOD1 protein. Currently, there is no effective treatment for this disease.

The principal investigator of the research is Prof. Stefania Corti, MD, PhD, associate professor of neurology, chief of the Neural Stem Cell Laboratory in the Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan.

Dr. Monica Nizzardo, the first of author of the paper, and colleagues demonstrated the feasibility and the therapeutic potential of silencing SOD1 protein expression in human ALS cells and in a ALS murine model. The researchers used an analogue of DNA, morpholino oligonucleotide, that inhibits SOD1 protein production and has a particularly excellent safety, distribution and efficacy profile. This strategy has been tested in a human model in culture, specifically in motor neurons (the cell-type affected in ALS) derived from induced pluripotent stem cells, obtained from skin fibroblasts of SOD1 familial and sporadic ALS patients. Morpholino treatment improved pathological phenotype increasing cell survival. Moreover, Morpholino has been injected in a murine model of ALS obtaining promising results in terms of disease progression, neuromuscular function and survival.

This study provides a relevant background for the development of morpholino-mediated therapy for ALS and for other neurodegenerative diseases.

The research was conducted with the support of AriSLA (Fondazione Italiana di ricerca per la SLA), Pilot Grant ALSsiMO to Dr. Nizzardo and with the support of Associazione Amici del “Centro Dino Ferrari”.

 For further information:

Dr. Monica Nizzardo

Centro Dino Ferrari, Università degli Studi di Milano, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico

Tel. +3902 55033833

monica.nizzardo1@gmail.com

Prof. Stefania Corti

Centro Dino Ferrari, Università degli Studi di Milano, IRCCS Fondazione Ca’ Granda Ospedale Maggiore Policlinico

Tel. +3902 55033817

stefania.corti@unimi.it

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