Gene Therapy

There are various limitations when it comes to therapeutic approaches to achieve localized increased mRNA expression in diseased target tissues. The delivery system has to overcome several challenges and barriers in order to efficiently target the diseased tissue. One of the main barriers is presented by the vascular endothelium and glycocalyx since the bloodstream must be navigated for the delivery system and therapeutic cargo to reach the diseased target tissue. Additionally, there is the cellular barrier, which poses a limitation in cDNA, mRNA or siRNA uptake, since the genetic code has to be internalized into the cytosol. Aside from the cell membrane being a barrier for RNA vehicles, endosomes are potentially degrading their content as soon as they fuse with the lysosome.

Based on CAR’s previously demonstrated ability to enhance the localized concentrations and therapeutic efficacy of co-administered small molecule drugs, we hypothesized that coadministration of CAR peptide would improve the disease-selective targeting of an adenovirus delivery vector.

We found that co-administering a single dose of CAR with an adenovirus gene delivery vector increased localized expression of the target mRNA 7-fold in a rat model of pulmonary hypertension. These results, in combination with prior findings that CAR also selectively augments a wide range of small molecule drugs for multiple diseases, suggests that this disease-targeting adjuvant strategy could be extended to selectively enhance other RNA therapeutics, such as mRNA and siRNA, and for other diseases as well.

One of the great advantages of the CAR peptide platform, in addition to high selectivity for diseased tissues, is that CAR peptide can simply be co-administered as an adjuvant with therapeutics without requiring physical conjugation between CAR and the therapeutic. This greatly accelerates the development time and cost to create targeted versions of existing therapeutics and therapeutic platforms.

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