Next-generation muscle-directed gene therapy by in silico vector design

There is an urgent need to develop the next-generation vectors for gene therapy of muscle disorders, given the relatively modest advances in clinical trials. These vectors should express substantially higher levels of the therapeutic transgene, enabling the use of lower and safer vector doses. In th...

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Bibliographic Details
Published in:	Nature communications Vol. 10; no. 1; p. 492
Main Authors:	Sarcar, S., Tulalamba, W., Rincon, M. Y., Tipanee, J., Pham, H. Q., Evens, H., Boon, D., Samara-Kuko, E., Keyaerts, M., Loperfido, M., Berardi, E., Jarmin, S., In’t Veld, P., Dickson, G., Lahoutte, T., Sampaolesi, M., De Bleser, P., VandenDriessche, T., Chuah, M. K.
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 30-01-2019 Nature Publishing Group Nature Portfolio
Subjects:	38 38/15 38/39 38/77 42 42/44 59/5 631/208/199 631/61/201 64/60 692/699/375/374 82/29 82/80 Animals Apoptosis Apoptosis - genetics Apoptosis - physiology Binding sites Clinical trials Computational Biology - methods Data mining Data processing Dystrophin Expression vectors Follistatin Gene therapy Genetic Therapy - methods Genetic Vectors - genetics Genomes Humanities and Social Sciences Humans Immune response Immune system Male Medical research Mice Mice, SCID multidisciplinary Muscle, Skeletal - metabolism Muscles Mutation - genetics Promoter Regions, Genetic - genetics Science Science (multidisciplinary) Vectors (Biology)
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Summary:	There is an urgent need to develop the next-generation vectors for gene therapy of muscle disorders, given the relatively modest advances in clinical trials. These vectors should express substantially higher levels of the therapeutic transgene, enabling the use of lower and safer vector doses. In the current study, we identify potent muscle-specific transcriptional cis -regulatory modules ( CRMs ), containing clusters of transcription factor binding sites, using a genome-wide data-mining strategy. These novel muscle-specific CRMs result in a substantial increase in muscle-specific gene transcription (up to 400-fold) when delivered using adeno-associated viral vectors in mice. Significantly higher and sustained human micro-dystrophin and follistatin expression levels are attained than when conventional promoters are used. This results in robust phenotypic correction in dystrophic mice, without triggering apoptosis or evoking an immune response. This multidisciplinary approach has potentially broad implications for augmenting the efficacy and safety of muscle-directed gene therapy. Adeno-associated viral vectors (AAV) are being developed for gene therapy of skeletal muscle, but it is a challenge to achieve robust gene expression. Here, the authors identify muscle-specific cisregulatory elements that lead to a substantial increase in micro-dystrophin and follistatin expression, resulting in a safe and sustainable rescue of the dystrophic phenotype in mouse models.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2041-1723 2041-1723
DOI:	10.1038/s41467-018-08283-7