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Clin Ther. 2014 Mar 1;36(3):340-56.e5. doi: 10.1016/j.clinthera.2014.02.004.

Effect of combined systemic and local morpholino treatment on the spinal muscular atrophy Δ7 mouse model phenotype.

Author information

1
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
2
Department of Chemistry and Biochemistry, University of Bern, Bern, Switzerland.
3
Biomedical Sciences, College of Veterinary Medicine, Oregon State University, Corvallis, Oregon.
4
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; IRCCS Eugenio Medea, Bosisio Parini, Lecco, Italy.
5
Dino Ferrari Centre, Neuroscience Section, Department of Pathophysiology and Transplantation, University of Milan, Neurology Unit, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Electronic address: stefania.corti@unimi.it.

Abstract

BACKGROUND:

Spinal muscular atrophy (SMA) is a fatal motor neuron disease of childhood that is caused by mutations in the SMN1 gene. Currently, no effective treatment is available. One possible therapeutic approach is the use of antisense oligos (ASOs) to redirect the splicing of the paralogous gene SMN2, thus increasing functional SMN protein production. Various ASOs with different chemical properties are suitable for these applications, including a morpholino oligomer (MO) variant with a particularly excellent safety and efficacy profile.

OBJECTIVE:

We investigated a 25-nt MO sequence targeting the negative intronic splicing silencer (ISS-N1) 10 to 34 region.

METHODS:

We administered a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) in the SMAΔ7 mouse model and evaluated the effect and neuropathologic phenotype. We tested different concentrations (from 2 to 24 nM) and delivery protocols (intracerebroventricular injection, systemic injection, or both). We evaluated the treatment efficacy regarding SMN levels, survival, neuromuscular phenotype, and neuropathologic features.

RESULTS:

We found that a 25-nt MO sequence against the ISS-N1 region of SMN2 (HSMN2Ex7D[-10-34]) exhibited superior efficacy in transgenic SMAΔ7 mice compared with previously described sequences. In our experiments, the combination of local and systemic administration of MO (bare or conjugated to octaguanidine) was the most effective approach for increasing full-length SMN expression, leading to robust improvement in neuropathologic features and survival. Moreover, we found that several small nuclear RNAs were deregulated in SMA mice and that their levels were restored by MO treatment.

CONCLUSION:

These results indicate that MO-mediated SMA therapy is efficacious and can result in phenotypic rescue, providing important insights for further development of ASO-based therapeutic strategies in SMA patients.

KEYWORDS:

SMAΔ7 mice; morpholino oligomer; spinal muscular atrophy; survival motor neuron; therapy

PMID:
24636820
DOI:
10.1016/j.clinthera.2014.02.004
[Indexed for MEDLINE]

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