Non-Viral Nucleic Acid Delivery Strategies to the Central Nervous System

Abstract

With an increased prevalence and understanding of central nervous system (CNS) injuries and neurological disorders, nucleic acid therapies are gaining promise as a way to regenerate lost neurons or halt disease progression. While more viral vectors have been used clinically as tools for gene delivery, non-viral vectors are gaining interest due to lower safety concerns and the ability to deliver all types of nucleic acids. Nevertheless, there are still a number of barriers to nucleic acid delivery. In this focused review, we explore the in vivo challenges hindering non-viral nucleic acid delivery to the CNS and the strategies and vehicles used to overcome them. Advantages and disadvantages of different routes of administration including: systemic injection, cerebrospinal fluid injection, intraparenchymal injection and peripheral administration are discussed. Non-viral vehicles and treatment strategies that have overcome delivery barriers and demonstrated in vivo gene transfer to the CNS are presented. These approaches can be used as guidelines in developing synthetic gene delivery vectors for CNS applications and will ultimately bring non-viral vectors closer to clinical application.

Keywords: central nervous system; delivery; in vivo; non-viral; nucleic acid.

Figure 1

Stages of nucleic acid delivery into a cell. Nucleic acids are typically condensed and complexed with a cationic material. This complex must be recognized by a cell, be internalized and escape the endosomal-lysosomal degradation pathway. Once in the cell cytoplasm, the nucleic acid can separate from its vehicle and traffic to its intended target based on its type.

Figure 2

Mechanisms of entering the central nervous system (CNS). (A) With receptor-mediated endocytosis, the binding of a ligand to its receptor on the brain endothelium facilitates cellular endocytosis, vesicular trafficking and eventually exocytosis on the contralateral side into the brain. (B) Microbubble-mediated disruption of the choroid plexus epithelium breaks tight junctions and creates micropores, allowing for the enhanced penetration of polyplexes into the brain. (C) New targeting ligands allow for uptake by peripheral neurons and the retrograde transport of cargo along axons to cell bodies in the CNS.