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

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Abstract
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 cisregulatory 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.
Keywords
MUSCULAR-DYSTROPHY, SKELETAL-MUSCLE, TRANSCRIPTIONAL MODULES, CANINE, MODEL, EXPRESSION, DELIVERY, AAV, TRANSDUCTION, PROMOTERS, MICE

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MLA
Sarcar, S et al. “Next-generation Muscle-directed Gene Therapy by in Silico Vector Design.” NATURE COMMUNICATIONS 10 (2019): n. pag. Print.
APA
Sarcar, S., Tulalamba, W., Rincon, M., Tipanee, J., Pham, H., Evens, H., Boon, D., et al. (2019). Next-generation muscle-directed gene therapy by in silico vector design. NATURE COMMUNICATIONS, 10.
Chicago author-date
Sarcar, S, W Tulalamba, MY Rincon, J Tipanee, HQ Pham, H Evens, D Boon, et al. 2019. “Next-generation Muscle-directed Gene Therapy by in Silico Vector Design.” Nature Communications 10.
Chicago author-date (all authors)
Sarcar, S, W Tulalamba, MY Rincon, J Tipanee, HQ Pham, H Evens, D Boon, E Samara-Kuko, M Keyaerts, M Loperfido, E Berardi, S Jarmin, P In’t Veld, G Dickson, T Lahoutte, M Sampaolesi, Pieter De Bleser, T VandenDriessche, and MK Chuah. 2019. “Next-generation Muscle-directed Gene Therapy by in Silico Vector Design.” Nature Communications 10.
Vancouver
1.
Sarcar S, Tulalamba W, Rincon M, Tipanee J, Pham H, Evens H, et al. Next-generation muscle-directed gene therapy by in silico vector design. NATURE COMMUNICATIONS. 2019;10.
IEEE
[1]
S. Sarcar et al., “Next-generation muscle-directed gene therapy by in silico vector design,” NATURE COMMUNICATIONS, vol. 10, 2019.
@article{8619582,
  abstract     = {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 cisregulatory 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.},
  articleno    = {492},
  author       = {Sarcar, S and Tulalamba, W and Rincon, MY and Tipanee, J and Pham, HQ and Evens, H and Boon, D and Samara-Kuko, E and Keyaerts, M and Loperfido, M and Berardi, E and Jarmin, S and In't Veld, P and Dickson, G and Lahoutte, T and Sampaolesi, M and De Bleser, Pieter and VandenDriessche, T and Chuah, MK},
  issn         = {2041-1723},
  journal      = {NATURE COMMUNICATIONS},
  keywords     = {MUSCULAR-DYSTROPHY,SKELETAL-MUSCLE,TRANSCRIPTIONAL MODULES,CANINE,MODEL,EXPRESSION,DELIVERY,AAV,TRANSDUCTION,PROMOTERS,MICE},
  language     = {eng},
  pages        = {16},
  title        = {Next-generation muscle-directed gene therapy by in silico vector design},
  url          = {http://dx.doi.org/10.1038/s41467-018-08283-7},
  volume       = {10},
  year         = {2019},
}

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