Novel synthetic regulation of gene expression
Gene therapy is an emerging market that is expected to grow at an astounding annual rate of 48.9%. Although gene therapies have yet to be approved in the United States, several are currently being evaluated in over 4,900 clinical trials – of which many are backed by major pharmaceutical companies like Pfizer and GSK. A major challenge of gene therapy is to target only the intended cell- and/or tissue-type. For this reason, many gene therapies are delivered using adeno-associated virus (AAV) vectors with gene-specific promoters; however, off-target AAV tropism and inadequate promoter regulation many times lead to the expression of the delivered gene in unintended cells/tissues. For these reasons, methods that can restrict the expression of the delivered gene within specific cells/tissues are needed for the safe implementation of gene therapy.
Drs. Marengo and Garcia-Blanco have recently developed a technique that promotes the stringent control of gene expression within specific cell types by combining gene-specific promoters with cell type-specific splicing exons and microRNA-binding sites. This invention has the potential to enhance the stringency of AAV-delivered gene therapies, or it could be utilized in stand-alone nucleic acid delivery systems (e.g. nanoparticle-, lipofection-, electroporation-mediated delivery). The latter would overcome several of the limitations of viral-based gene therapies, including immunological neutralization by the host and restrictions on transgene size.
This methodology enforces multiple modes of cell
–specific transcriptional regulation before the desired gene can be encoded, thereby preventing “leaky” expression within unintended cell types.