Lysosomal Storage Disease-Associated Neuropathy: Targeting Stable Nucleic Acid Lipid Particle (SNALP)-Formulated siRNAs to the Brain as a Therapeutic Approach

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.

Spherical nucleic acids: emerging amplifiers for therapeutic nanoplatforms

“…Traditional nucleic acid delivery systems have many drawbacks such as low encapsulation efficiency, poor transfection effects, and strong immune response. [24][25][26] Moreover, the structure of many nanocarriers only allows nucleic acids to be encapsulated inside, 27,28 which hides the unique advantages of many nucleic acids such as denaturation, renaturation, and hybridization abilities. SNAs overcome the prior structural constraints characteristic of traditional gene therapy.…”

Oligonucleotide-Based Therapeutics for STAT3 Targeting in Cancer—Drug Carriers Matter

“…The binding of oligonucleotides to SNALPs reduced oligonucleotide-dependent toxicity by lowering the required dose of oligonucleotide-based therapeutics [113]. Numerous studies on therapeutic oligonucleotide delivery efficiency, toxicity, and half-life activity in mice and non-human primate models indicated that SNALPs are promising nanoparticles [115][116][117][118].…”

Recent Advances in RNA Therapy and Its Carriers to Treat the Single-Gene Neurological Disorders

“…Extracellular vesicles (EVs) have also been used to effectively deliver functional GLA to cells in Fabry disease models [ 180 ]. Another class of special liposomes called stable nucleic acid lipid particles (SNALPs) has been found as a promising platform for delivering small RNA molecules [ 181 ]. SNALPs are characterized by the high efficiency of cargo encapsulation and can be engineered to target specific receptors.…”