Controlled release strategies for rAAV-mediated gene delivery

Abstract

The development of efficient and safe gene transfer vectors capable of achieving appropriate levels of therapeutic gene expression in a target is one of the most challenging issues in clinical gene therapy. Diverse nonviral and viral gene vehicles have been developed to modify human cells and tissues that may be affected in a variety of diseases, among which the nonpathogenic, effective, and relatively safe recombinant adeno-associated viral (rAAV) vectors that make them a preferred gene delivery system to treat human disorders. Yet, their adapted clinical application is still limited by several hurdles including the presence of immune responses in the host organism and the existence of rate-limiting steps associated with physiological barriers. The use of controlled release strategies to deliver gene vectors such as rAAV may provide powerful tools to enhance the temporal and spatial presentation of therapeutic agents in a defined target and to overcome such obstacles in vivo. The goal of this review is to provide an overview of the most recent advances in gene therapy with a focus on rAAV vectors for clinical translation based on the controlled release from adapted biomaterials as a means to improve the performance of the gene transfer procedure. We also discuss the challenges that remain to be addressed for a safe and efficient adaptation and use of such approaches in the patient.

Statement of significance: The development of effective gene vectors to achieve suitable levels of a therapeutic agent in a target is a critical issue in clinical gene therapy and regenerative medicine. Diverse vehicles are currently available among which the nonpathogenic recombinant adeno-associated virus (rAAV) vectors, a preferred system to effectively treat human disorders. Yet, the clinical use of rAAV is impaired by the host immune responses and by rate-limiting steps of transgene expression. Controlled rAAV delivery systems may provide workable approaches to overcome such obstacles. Here, we give an overview of the most recent advances on the controlled release of vectors with a focus on rAAV using adapted biomaterials and discuss the key challenges for a safe translation in patients.

Keywords: Controlled release; Human gene therapy; rAAV.