Abstract
Nanoparticles with oligonucleotides bound to the outside or incorporated into the matrix can be used for gene editing or to modulate gene expression in the CNS. These nanocarriers are usually optimised for transfection of neurons or glia. They can also facilitate transcytosis across the brain endothelium to circumvent the blood-brain barrier. This review examines the different formulations of nanocarriers and their oligonucleotide cargoes, in relation to their ability to enter the brain and modulate gene expression or disease. The size of the nanocarrier is critical in determining the rate of clearance from the plasma as well as the intracellular routes of endothelial transcytosis. The surface charge is important in determining how it interacts with the endothelium and the target cell. The structure of the oligonucleotide affects its stability and rate of degradation, while the chemical formulation of the nanocarrier primarily controls the location and rate of cargo release. Due to the major anatomical differences between humans and animal models of disease, successful gene therapy with oligonucleotides in humans has required intrathecal injection. In animal models, some progress has been made with intraventricular or intravenous injection of oligonucleotides on nanocarriers. However, getting significant amounts of nanocarriers across the blood-brain barrier in humans will likely require targeting endothelial solute carriers or vesicular transport systems.
Highlights
Antisense igonucleotides (ASOs) binding to the primary transcript can ribosomal assembly or translation (3)
ASOs binding to the primary transcript can inhibit cap formation (4), polyadenylation or splicing (5), with the potential to act as a substrate for inhibit cap formation
The chemical modification of nucleic acids has substantially improved the resistance of oligonucleotides to nucleases, but it may reduce the effectiveness of the nucleotide if it must interact with cellular RNA processing machinery
Summary
The development of gene therapy has opened up prospects for the treatment of diseases that affect the central nervous system [1,2]. Viral vectors are most suitable for delivery of entire genes to cells of the CNS, and this approach has achieved some success with adeno-associated viruses (AAVs), which can hold up to 5 kBa DNA [4]. The first-generation vectors were mostly optimised for transfection of cells, gene integration and expression, rather than their ability to cross the blood-brain barrier For this reason, delivery of the viral vectors has often been by direct intrathecal or intraventricular injection. Protect the nucleic acid against enzymatic degradation, Non-toxic and low immunogenicity, Selective internalisation into the target cells of the CNS, Release of the nucleic acid and appropriate expression or activity in that cell type These considerations apply to any nanocarrier that is directly injected into the CNS.
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