1057. Generating Efficient Promoters for Cardiovascular Gene Therapy Using Synthetic Promoter Libraries

Abstract

Optimised promoters would be beneficial to maximise long-term transgene expression in vivo and improve gene therapy efficiency. Viral promoters can achieve high-level constitutive transgene expression in most mammalian cell types, however they are non-selective and sensitive to silencing in vivo via methylation, hampering efficacy for long-term expression of certain transgenes. Candidate mammalian promoters have been investigated as possible alternatives for cell-selective transcription, however many produce low-level transcriptional activity, or their size precludes their insertion into viral gene delivery vectors. We are developing synthetic promoter elements via the rational design and random combination of transcriptional regulating elements (TREs) linked to a basal promoter element for regulated transcription in skeletal or cardiac muscle under conditions of oxidative stress, a significant pathophysiological phenomenon that contributes to the development of varied cardiovascular diseases.