Somatic therapy of a mouse SMA model with a U7 snRNA gene correcting SMN2 splicing

Odermatt, Philipp; Trüb, Judith; Furrer, Lavinia; Fricker, Roger; Marti, Andreas; Schümperli, Daniel (2016). Somatic therapy of a mouse SMA model with a U7 snRNA gene correcting SMN2 splicing. Molecular therapy, 24(10), pp. 1797-1805. Nature Publishing Group 10.1038/mt.2016.152

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Spinal Muscular Atrophy (SMA) is due to the loss of SMN1 gene function. The duplicate gene SMN2 produces some, but not enough, SMN protein because most transcripts lack exon 7. Thus, promoting the inclusion of this exon is a therapeutic option. We show that a somatic gene therapy using the gene for a modified U7 RNA which stimulates this splicing has a profound and persistent therapeutic effect on the phenotype of a severe SMA mouse model. To this end, the U7 gene and vector and the production of pure, highly concentrated self-complementary (sc) AAV9 vector particles were optimized. Introduction of the functional vector into motoneurons of newborn SMA mice by intracerebroventricular injection led to a highly significant, dose-dependent increase in life span and improvement of muscle functions. Besides the central nervous system, the therapeutic U7 RNA is expressed in the heart and liver which may additionally contribute to the observed therapeutic efficacy. This approach provides an additional therapeutic option for SMA and could also be adapted to treat other diseases of the central nervous systems with regulatory small RNA genes.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Department of Biology > Institute of Cell Biology
08 Faculty of Science > Departement of Chemistry and Biochemistry
08 Faculty of Science > Department of Biology > Institute of Cell Biology > RNA

Graduate School:

Graduate School for Cellular and Biomedical Sciences (GCB)

UniBE Contributor:

Odermatt, Philipp; Trüb, Judith; Marti, Andreas and Schümperli, Daniel

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1525-0016

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Daniel Schümperli

Date Deposited:

05 Aug 2016 14:16

Last Modified:

05 Dec 2016 08:00

Publisher DOI:

10.1038/mt.2016.152

PubMed ID:

27456062

BORIS DOI:

10.7892/boris.85266

URI:

https://boris.unibe.ch/id/eprint/85266

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