Synthetic muscle promoters: activities exceeding naturally occurring regulatory sequences

Li, Xuyang; Eastman, Eric; Schwartz, Robert J.; Draghia-Akli, Ruxandra

doi:10.1038/6981

Cited by 212 publications

(167 citation statements)

References 23 publications

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“…Of the non-viral promoters employed, some such as b actin have general activity within eukaryote cells. 30,31 Some promoters control expression in a cell-or tissue-specific manner eg a skeletal muscle actin promoter, 32 myosin light chain 3F promoter 33 and muscle creatine kinase (MCK) promoter 34 which are activated specifically in muscle. The best example of promoters of high cell specificity is the ventricle-specific myosin light chain-2 which is activated exclusively in cardiac myocytes.…”

Section: Promoter Enhancer and Other Elementsmentioning

confidence: 99%

“…Li et al assembled these elements randomly into synthetic promoter recombinant libraries and screened hundreds of individual clones for transcriptional activity both in vitro and in vivo. 30 Several artificial promoters were isolated whose transcriptional potencies exceed those of natural myogenic and viral gene promoters.…”

Section: Promoter Enhancer and Other Elementsmentioning

confidence: 99%

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Non-viral gene delivery in skeletal muscle: a protein factory

Lu¹,

Bou‐Gharios²,

Partridge³

2003

Gene Ther

168

109

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Ever since the publication of the first reports in 1990 using skeletal muscle as a direct target for expressing foreign transgenes, an avalanche of papers has identified a variety of proteins that can be synthesized and correctly processed by skeletal muscle. The impetus to the development of such applications is not only amelioration of muscle diseases, but also a range of therapeutic applications, from immunization to delivery of therapeutic proteins, such as clotting factors and hormones. Although the most efficient way of introducing transgenes into muscle fibres has been by a variety of recombinant viral vectors, there are potential benefits in the use of non-viral vectors. In this review we assess the recent advances in construction and delivery of naked plasmid DNA to skeletal muscle and highlight the options available for further improvements to raise efficiency to therapeutic levels.

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Section: Promoter Enhancer and Other Elementsmentioning

confidence: 99%

Section: Promoter Enhancer and Other Elementsmentioning

confidence: 99%

Non-viral gene delivery in skeletal muscle: a protein factory

Lu¹,

Bou‐Gharios²,

Partridge³

2003

Gene Ther

168

109

View full text Add to dashboard Cite

show abstract

“…An interesting and more extreme approach would be to generate a complete synthetic promoter by multimerization and shuffling of known regulatory elements, then selecting the most active and properly regulated construct. This approach has been applied to the chicken skeletal α-actin promoter to achieve muscle-specific expression that exceeds the level of the CMV promoter [43].Two strategies have frequently been employed to amplify weak promoter activity in a twotiered manner (Figure 2). In an approach known as 'two-step transcriptional activation' (TSTA, Figure 2a), the specific promoter directed the potent transcription activator, GAL4-VP16, which in turn acted upon a second GAL-4-responsive reporter or therapeutic gene.…”

mentioning

confidence: 99%

Transcriptionally targeted gene therapy to detect and treat cancer

Wu¹,

Johnson²,

Sato³

2003

Trends in Molecular Medicine

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The greatest challenge in cancer treatment is to achieve the highest levels of specificity and efficacy. Cancer gene therapy could be designed specifically to express therapeutic genes to induce cancer cell destruction. Cancer-specific promoters are useful tools to accomplish targeted expression; however, high levels of gene expression are needed to achieve therapeutic efficacy. Incorporating an imaging reporter gene in tandem with the therapeutic gene will allow tangible proof of principle that gene expression occurs at the correct location and at a sufficient level. Gene-based imaging can advance cancer detection and diagnosis. By combining the cancer-targeted imaging and therapeutic strategies, the exciting prospect of a 'one-two punch' to find hidden, disseminated cancer cells and destroy them simultaneously can potentially be realized.Multiple genetic alterations that confer growth advantages to tumor cells are accumulated during the transformation from normal to neoplastic growth [1]. The loss of growth suppressive genes or gain of oncogenes constitutes a common mechanism of oncogenesis. Based on this information, a rational therapeutic approach is to re-introduce the defective growth control genes into tumor cells. In addition, approaches of inducing apoptotic responses and enhancing anti-tumor immune responses have also been employed [2]. Due to the availability of multiple flexible therapeutic strategies, gene therapy is being actively investigated in clinical settings.Among the ~ 40 ongoing gene therapy clinical trials for cancer (searched via www.clinicaltrials.gov/), 18 of the trial protocols involve an immune activating scheme, ten studies employ a genetic correction strategy and five use a cytotoxic gene. With regard to genetic correction strategies, p53 is a major target. The recombinant adenovirus is the dominant viral gene delivery vector, and it is employed in 18 protocols. However, none of 40 protocols use a cancer-specific gene expression strategy. An oncolytic adenovirus CN706 containing prostate-specific antigen (PSA) promoter driven viral replication [3] is being evaluated in phase II clinical trial for prostate cancer [4].Because the goal of cancer gene therapy is to eradicate cancer cells, many therapeutic genes could be detrimental if unintentionally expressed in normal cells. Selectively targeting the cancer cells is useful to achieve safety and efficacy, especially when the gene therapy vector is directly delivered into patients. Based on features that distinguish cancerous from normal cells, three targeting strategies could be employed. Transcriptional targeting takes advantage of the fact that some cancer cells express a subset of exclusive genes, and uses these cancerspecific promoters to express the desired transgenes [5]. Transductional targeting refers to surface modification on the gene delivery vehicle to enhance interactions with the cancer cell membrane antigen, thereby improving gene transfer into the cancerous cell. A third promising approach is to exploit cancer-a...

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“…9 Recent efforts to produce an optimal promoter for muscle expression using shuffling of a wide variety of promoter elements resulted in only an eight-fold increase in promoter activity over the starting construct. 23 Using a directed approach we have been able to produce a 20-fold increase over the Factor IX promoter alone.…”

Section: Discussionmentioning

confidence: 99%