ABSTRACT
Antisense oligomers (ASOs) are short strands (typically 20bp in length) of deoxyribonucleotides that, upon intracellular delivery, hybridize to specifi c mRNAs and cause reduced expression of the encoded proteins (Chan et al. 2006). ASOs represent a powerful strategy for gene validation and for the cure of diseases associated to dysregulated protein expression, such as autoimmune diseases and cancer. Several chemical modifi cations of ASOs have been developed which dramatically improved their resistance to nucleases, circulation half-life, affi nity for mRNA and silencing potency compared to fi rst-generation oligos. However, a persisting limitation to the use of ASOs in vivo is their low spontaneous cell-permeability, especially in certain cell types. Several approaches based on physical methods (e.g., electroporation) or the use of delivery agents (e.g., viral vectors and cationic liposomes) are available to ensure effi cient introduction of ASOs into cells in culture. However, comparable systems for in vivo application are still in the early stages of development, and the vast majority of ASOs undergoing clinical trials for FDA-approval are topically or systemically administered in “free” form. There is a critical need for novel delivery systems to enable the safe delivery of ASOs to targeted cells and tissues after systemic administration. Innovative solutions in this fi eld are coming from nanomedicine, a discipline recently born from the marriage of nanotechnology and medicine. Through the use of nanotechnology-derived composites (nanocarriers), nanomedicine helps traditional drugs avoid the biological and biophysical barriers the drug encounters following its systemic administration. In this chapter we will describe diabetes-relevant applications of nanocarriers as delivery systems for ASOs. We divided the
chapter in two sections. In the fi rst section we will summarize the modes of action of ASOs and the chemical modifi cations that have been developed to ameliorate the resistance to nucleases, enhance affi nity and potency, and reduce toxicity (§ 2.1.), the biological barriers encountered by ASOs following their systemic administration (§ 2.2. and § 2.3.) and the range of solutions that nanomedicine can offer to enable the safe delivery of ASOs to the target site (§ 2.4. and § 2.5). In the second section, we will review ASOs and delivery systems that have been developed for applications in the diabetes fi eld. This includes research from our laboratory focused on achieving targeted delivery of ASOs into T cells for therapy of Type 1 Diabetes.
