Gene-Therapy Delivery Strategies in Cardiology

Abstract

Clinical gene-therapy approaches in cardiology have not fulfilled their promise in randomized, controlled trials, so far, despite striking effects in preclinical models. Lack of clinical success appears not to be related to an unexpected low potency of the therapeutic factors itself in humans, but has rather been attributed to limitations of the vector systems used to transfer the DNA, as well as application modes of the vector itself. Therefore, novel delivery strategies are required with increased efficiency and increased specificity. Recent improvements of vectors using targeting approaches in addition to the development of novel application strategies for cardiac or vascular gene transfer will improve gene delivery in future clinical approaches.

Genetically Encoded Ca 2+ Indicators in Cardiac Myocytes

“…Although direct injections may lead to a patchy transduction pattern, transvascular or systemic application approaches have the advantage of a more homogeneous cardiac transduction but face additional obstacles, such as neutralizing antibodies, binding to plasma proteins in the circulation, and effective passage through the vascular wall. 35 Furthermore, transduction efficiency depends on successful uptake into cardiomyocytes. Finally, sustained expression of the transgene depends on the ability of the vector to prevent clearance of its vector genome in the cell and the lack of an immune response against vector epitopes.…”

“…Its low immunogenicity enables a sustained gene transfer in rodents. 35 Certain naturally occurring AAV serotypes, such as serotype 9 vectors, resulted in uniform and extensive cardiac transfer in adult mice after intravenous injections. [42][43][44][45][46] Although further modifications of the AAV-vector surface (educated guess or library-based approaches) could extend the tropism of gene transfer, for example, to vessels or increase specificity, AAV9 vectors still remain the vector of choice for systemic cardiac gene transfer in rodents.…”

The Road Ahead: Working Towards Effective Clinical Translation of Myocardial Gene Therapies

“…The main challenges facing the vector are as follows: ■ Escaping the neutralizing effects of specific antibodies and nonspecific adsorption to other blood components;■ Overcoming the endothelial barrier and penetrating the vascular wall for diffusion through the extracellular matrix;■ Uptake into the cell at the level of the plasma membrane and efficient trafficking to the nucleus;■ Synthesis by the host of the complementary DNA strand for single-stranded delivery vectors followed by transcription and translation of the transgene [6]. …”

“…■ Synthesis by the host of the complementary DNA strand for single-stranded delivery vectors followed by transcription and translation of the transgene [6]. …”