Abstract
More than two thirds of Lysosomal Storage Diseases (LSDs) present central nervous system involvement. Nevertheless, only one of the currently approved therapies has an impact on neuropathology. Therefore, alternative approaches are under development, either addressing the underlying enzymatic defect or its downstream consequences. Also under study is the possibility to block substrate accumulation upstream, by promoting a decrease of its synthesis. This concept is known as substrate reduction therapy and may be triggered by several molecules, such as small interfering RNAs (siRNAs). siRNAs promote RNA interference, a naturally occurring sequence-specific post-transcriptional gene-silencing mechanism, and may target virtually any gene of interest, inhibiting its expression. Still, naked siRNAs have limited cellular uptake, low biological stability, and unfavorable pharmacokinetics. Thus, their translation into clinics requires proper delivery methods. One promising platform is a special class of liposomes called stable nucleic acid lipid particles (SNALPs), which are characterized by high cargo encapsulation efficiency and may be engineered to promote targeted delivery to specific receptors. Here, we review the concept of SNALPs, presenting a series of examples on their efficacy as siRNA nanodelivery systems. By doing so, we hope to unveil the therapeutic potential of these nanosystems for targeted brain delivery of siRNAs in LSDs.
Highlights
When, in 1998, Fire and Mello published their first discovery of double-stranded RNAs, which were able to trigger gene-silencing in Caenorhabditis elegans, acting as gene function regulators [1], no one realized we were looking at one of the last great advances in cell biology
We hope to unveil the therapeutic potential of these small interfering RNAs (siRNAs) nanodelivery systems for targeted brain delivery in a series of rare but life-threatening genetic pathologies, which have been our research focus over recent decades, the so-called Lysosomal Storage Diseases (LSDs)
The clinical application of this sort of drugs largely depends on the development of appropriate delivery systems, which are able to ameliorate the unfavorable pharmacokinetics of RNA interference (RNAi) effectors, while enhancing their biodistribution properties
Summary
In 1998, Fire and Mello published their first discovery of double-stranded RNAs, which were able to trigger gene-silencing in Caenorhabditis elegans, acting as gene function regulators [1], no one realized we were looking at one of the last great advances in cell biology. We discuss its application in a substrate reduction therapy for a group of genetic disorders characterized by intralysosomal accumulation of undegraded materials, where brain pathology remains a challenge even though some therapeutic approaches are available mainly for systemic pathology. As it happens with many other disorders, translation of one such approach into the clinical setting largely depends on the development of appropriate systems for targeted delivery, which allow for proper biodistribution and promote more favorable pharmacokinetics. We hope to unveil the therapeutic potential of these siRNA nanodelivery systems for targeted brain delivery in a series of rare but life-threatening genetic pathologies, which have been our research focus over recent decades, the so-called Lysosomal Storage Diseases (LSDs)
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