Enriched chitosan nanoparticles loaded with siRNA are effective in lowering Huntington's disease gene expression following intranasal administration

Abstract

Therapies to lower gene expression in brain disease currently require chronic administration into the cerebrospinal fluid (CSF) by intrathecal infusions or direct intracerebral injections. Though well-tolerated in the short-term, this approach is not tenable for a life-time of administration. Nose-to-brain delivery of enriched chitosan-based nanoparticles loaded with anti-HTT siRNA was studied in a transgenic YAC128 mouse model of Huntington's Disease (HD). A series of chitosanbased nanoparticle (NP) formulations encapsulating anti-HTT small interfering RNA (siRNA) were designed to protect the payload from degradation "en route" to the target. Factors to improve production of effective nanocarriers of anti-HTT siRNA were identified and tested in a YAC128 mouse model of Huntington's disease. Four formulations of nanocarriers were identified to be effective in lowering HTT mRNA expression by at least 50%. Intranasal administration of nanoparticles carrying siRNA is a promising therapeutic alternative for safe and effective lowering of mutant HTT expression.

Advances in Chitosan-Based Nanoparticles for Drug Delivery

“…Though well-tolerated in the short term, this approach is not tenable for a lifetime of administration. Sava et al [189] synthesized enriched CS-based NPs loaded with anti-HTT small interfering RNA (siRNA) for nose-to-brain delivery. The NPs were studied in a transgenic YAC128 mouse model of HD.…”

Neurorepair and Regeneration of the Brain: A Decade of Bioscaffolds and Engineered Microtissue

“…Although genetic mutation responsible for HD is well know, there is still no treatment to stop or slow disease progression. Sava et al (2020) developed chitosan nanoparticles loaded with anti-huntingtin siRNA to treat an HD mouse model using the intranasal route. The authors developed four formulations of nanocarriers able to lower huntingtin mRNA expression by at least 50%.…”

Using nanotechnology to deliver biomolecules from nose to brain — peptides, proteins, monoclonal antibodies and RNA

“…A literature analysis of the influence of the surface charge on the capacity of nanocarriers to overcome the N-to-B barrier leads to the conclusion that it is the chemical composition of the surface, rather than its charge, the main factor influencing the interaction and transport of nanoparticles across the olfactory mucosa. In fact, different nanocarriers with surface charges from + 57 to − 30 mV have shown significant efficacy in enhancing N-to-B delivery of different biomolecules [108,[113][114][115]. For example, chitosan (positive charge)-and polysorbate-80 (negative charge)-coated polystyrene NPs were investigated for their transport across the murine olfactory epithelium.…”

“…In addition to the so-called CPPs, cationic polymers, notably chitosan, have also been explored for their penetration-enhancing properties in the form of nanoparticles. Chitosan nanoparticles have been used for the N-to-B delivery of different kinds of siRNA as commented in the following section [113,133]. Hybrid nanocarriers, combining chitosan with manganese or with gold NPs (AuNPs), have also been proven to enhance the delivery of multiple types of RNA to different brain areas [134,135].…”