RNAi has attracted many attentions in therapeutic studies since its discovery, and it is anticipated that RNAi-based therapeutics would rapidly reach the clinic in gene-based medicine research. However, there are still numerous unresolved challenges in nucleic acid-based technologies. And in order to realize the therapeutic potential of RNAi, strategies are being devised to avoid natural barriers to delivery, immune/non-immune toxicities and monitor delivery and therapeutic indices in real-time.
Brain barrier
Delivery of inhibitory RNAs to the CNS is a daunting task due to the blood–brain barrier. The most suitable RNAi delivery modality depends on our understanding of disease pathogenesis and the desired duration of gene silencing. Non-viral-delivered nucleic acids may access the CNS using three major entry routes: through the vasculature, cerebrospinal fluid or by direct intraparenchymal delivery into the brain. Thereby, the limiting factors include stability of the siRNA complexes and their capacity to penetrate target cells without activating immune responses.
Efforts have been made to address some of these challenges by focusing on incorporating chemical modifications into the sugars, backbone or bases of siRNA duplexes. Certain modifications help to increase stability thus effectively lowering the dose needed to achieve measurable and reproducible gene silencing. And there are still some internal modifications failing to improve CNS entry and uptake after systemic delivery. To date, new efforts have moved towards testing liposomes, nanoparticles and cell-penetrating peptides, among others, to stabilize and navigate siRNAs into and throughout the brain. Future studies will be focused on exploiting the presence of disease-related epitopes as a means to increase further the efficacy, specificity and potency of non-viral siRNA delivery to the brain. Finally, the potential for an adverse immune response to RNAi therapy is an important consideration. In general, innate immune responses to non-viral-delivered siRNAs are mediated by toll-like receptors or by two different dsRNA-sensing proteins, however, the use of chemically modified or nanoparticle-encased siRNA duplexes avoids stimulation of these pathways.
Inability to monitoring
Another challenge with the use RNAi is our limited ability to monitor, in real-time, the delivery, activity and specificity of an RNAi molecule in the brain. Post-treatment sampling is impractical in the brain and thus model systems are required to establish correlations between gene-silencing potency and dose-specific toxicity. Previously, biomarker particular to certain neurodegenerative disease is the best choice to monitor a coincident response to therapeutic RNAi, although for many disorders the validity of a given biomarker to represent a particular disease stage is far from known. But currently advancesin imaging techniques , such as the PCR technique, to track RNA in vivo with quantum dots are showing promise.The monitoring of RNAi will no longer be a problem in near future.
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