Designing gene therapy vectors: avoiding immune responses by using tissue-specific promoters

Weeratna, R. D.; Wu, Tong; Efler, SM; Zhang, L; Davis, H. L.

doi:10.1038/sj.gt.3301602

Cited by 55 publications

(35 citation statements)

References 27 publications

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“…18 In the present study, we delivered both human and murine full-length dystrophin cDNAs under the control of a CMV promoter. The CMV promoter allows the expression of the dystrophin transgene in many cell types, 36 including professional antigen-presenting cells (APCs). While the mechanism of crosspriming seems to be the most likely after intramuscular DNA injection, 37 it is probable that some APC present in the muscle are transfected and antigen expression in these APC primes MHC class I and II responses.…”

Section: Discussionmentioning

confidence: 99%

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

et al. 2004

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Section: Discussionmentioning

confidence: 99%

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

et al. 2004

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“…[6][7][8] The viral promoters, such as human cytomegalovirus (CMV) immediate-early gene promoter, achieve high levels of nonspecific gene expression; in contrast, the use of the muscle creatine kinase (MCK) promoter is specific to muscle tissue and can avoid the potentially harmful effects of ectopic transgene expression. [9][10][11][12] However, the MCK promoter is less active than viral promoters, and its large size (6.5 kb) makes it incompatible with adeno-associated viral (AAV) vectors, a noteworthy gene delivery vehicle with a 4.5-kb capacity for the treatment of muscular dystrophies and other degenerative disorders. [13][14][15] We have shown previously that a truncated MCK promoter (enh358MCK, 584-bp) could achieve musclespecific expression of the human minidystrophin genes (3.8-4.2 kb) in dystrophin-deficient mdx mice, ameliorate pathologies and improve muscle contractile function in mdx mice.…”

Section: Instructionmentioning

confidence: 99%

Construction and analysis of compact muscle-specific promoters for AAV vectors

et al. 2008

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Adeno-associated viral (AAV) vectors have been broadly used for gene transfer in vivo for various applications. However, AAV precludes the use of most of the original large-sized tissue-specific promoters for expression of transgenes. Efforts are made to develop highly compact, active and yet tissue-specific promoters for use in AAV vectors. In this study, we further abbreviated the muscle creatine kinase (MCK) promoter by ligating a double or triple tandem of MCK enhancer (206-bp) to its 87-bp basal promoter, generating the dMCK (509-bp) and tMCK (720-bp) promoters. The dMCK promoter is shorter but stronger than some previously developed MCK-based promoters such as the enh358MCK (584-bp) and CK6 (589-bp) in vitro in C2C12 myotubes and in vivo in skeletal muscles. The tMCK promoter is the strongest that we tested here, more active than the promiscuous cytomegalovirus (CMV) promoter. Furthermore, both the dMCK and tMCK promoters are essentially inactive in nonmuscle cell lines as well as in the mouse liver (4200-fold weaker than the CMV promoter).The dMCK promoter was further tested in a few lines of transgenic mice. Expression of LacZ or minidystrophin gene was detected in skeletal muscles throughout the body, but was weak in the diaphragm, and undetectable in the heart and other tissues. Similar to other miniature MCK promoters, the dMCK promoter also shows preference for fast-twitch myofibers. As a result, we further examined a short, synthetic muscle promoter C5-12 (312-bp). It is active in both skeletal and cardiac muscles but lacks apparent preference on myofiber types. Combination of a MCK enhancer to promoter C5-12 has increased its strength in muscle by two-to threefold. The above-mentioned compact muscle-specific promoters are well suited for AAV vectors in muscle-directed gene therapy studies.

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“…Although this is a legitimate explanation, cross-presentation does not appear to be a major route for CD8 ϩ T cell priming following i.m. injection of plasmid, which is the route used in the current study (34,35). Indeed, CD8…”

Section: Discussionmentioning

confidence: 99%

Electroporation Enables Plasmid Vaccines to Elicit CD8+ T Cell Responses in the Absence of CD4+ T Cells

Dayball

Millar

Miller

et al. 2003

The Journal of Immunology

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In vivo electroporation dramatically enhances plasmid vaccine efficacy. This enhancement can be attributed to increased plasmid delivery and, possibly, to some undefined adjuvant properties. Previous reports have demonstrated CD8+ T cell priming by plasmid vaccines is strongly dependent upon CD4+ T cell help. Indeed, the efficacy of a plasmid vaccine expressing Escherichia coli β-galactosidase was severely attenuated in MHC class II-deficient (C2D) mice. To determine whether electroporation could compensate for the absence of CD4+ T cell help, C2D mice were immunized by a single administration of plasmid in combination with electroporation using two conditions which differed only by the duration of the pulse (20 or 50 msec). Both conditions elicited robust cellular and humoral responses in wild-type mice, as measured by IFN-γ ELISPOT, anti-β-galactosidase ELISA, and protection from virus challenge. In C2D mice, the cellular response produced by the vaccine combined with the 50-msec pulse, as measured by ELISPOT, was identical to the response in wild-type mice. The 20-msec pulse elicited a milder response that was approximately one-fifth that of the response elicited by the 50-msec pulse. By contrast, the 20-msec conditions provided comparable protection in both wild-type and C2D recipients whereas the protection elicited by the 50-msec conditions in C2D mice was weaker than in wild-type mice. Further investigation is required to understand the discordance between the ELISPOT results and outcome of virus challenge in the C2D mice. Nonetheless, using this technique to prime CD8+ T cells using plasmid vaccines may prove extremely useful when immunizing hosts with limiting CD4+ T cell function, such as AIDS patients.

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Designing gene therapy vectors: avoiding immune responses by using tissue-specific promoters

Cited by 55 publications

References 27 publications

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

Long-term expression of full-length human dystrophin in transgenic mdx mice expressing internally deleted human dystrophins

Construction and analysis of compact muscle-specific promoters for AAV vectors

Electroporation Enables Plasmid Vaccines to Elicit CD8+ T Cell Responses in the Absence of CD4+ T Cells

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