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Delivery of Therapeutic siRNA to the CNS Using Cationic and Anionic Liposomes
Published on: July 23, 2016
Self-assembling modified β-cyclodextrin nanoparticles as neuronal siRNA delivery vectors: focus on Huntington's
Bruno M D C Godinho1, Julien R Ogier, Raphael Darcy
1Pharmacodelivery Group, School of Pharmacy, University College Cork , Cork, Ireland.
Molecular Pharmaceutics
|November 3, 2012
Summary
Modified cyclodextrins effectively deliver short interfering RNA (siRNA) to the brain, silencing the toxic Huntingtin protein. This breakthrough offers a promising, low-toxicity approach for Huntington's disease (HD) gene silencing therapy.
Area of Science:
- Neuroscience
- Molecular Biology
- Biotechnology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a toxic Huntingtin (HTT) protein.
- RNA interference (RNAi) using short interfering RNAs (siRNAs) is a potential therapeutic strategy.
- Efficient and safe delivery of siRNAs to the central nervous system (CNS) remains a significant challenge.
Purpose of the Study:
- To investigate modified amphiphilic β-cyclodextrins (CDs) as novel siRNA carriers for neuronal delivery.
- To evaluate the efficacy and safety of CD-siRNA nanoparticles for Huntington's disease therapy.
Main Methods:
- Formation and characterization of CD·siRNA nanoparticles.
- Assessment of nanoparticle stability in artificial cerebrospinal fluid.
- In vitro evaluation of HTT gene silencing in rat striatal cells and human HD fibroblasts.
- In vivo studies in the R6/2 mouse model of HD, including direct brain injections and assessment of motor deficits.
Main Results:
- CDs formed stable, nanosize particles suitable for CNS delivery.
- CD·siRNA nanoparticles effectively reduced HTT gene expression in vitro with limited toxicity.
- Single and repeated brain injections of CD·siRNA nanoparticles led to sustained HTT knockdown and alleviated motor deficits in HD mice.
Conclusions:
- Modified β-cyclodextrins are efficient and safe siRNA delivery vectors for the CNS.
- CD-based siRNA delivery holds significant potential for RNAi-based therapies targeting neurodegenerative and neuropsychiatric disorders like Huntington's disease.
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01:21Huntington Disease l: Introduction
Huntington disease or HD is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant pattern.PathophysiologyIt is caused by expansion of the CAG trinucleotide repeat in the HTT gene on chromosome 4 (4p16.3), producing an abnormal huntingtin protein with an expanded polyglutamine tract. This misfolded protein disrupts cellular function, leading to neuronal death. Normal alleles have ≤26 repeats, 27–35 are intermediate (risk of expansion), 36–39 show reduced penetrance,...
02:30siRNA - Small Interfering RNAs
Small interfering RNAs, or siRNAs, are short regulatory RNA molecules that can silence genes post-transcriptionally, as well as the transcriptional level in some cases. siRNAs are important for protecting cells against viral infections and silencing transposable genetic elements.
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...
In the cytoplasm, siRNA is processed from a double-stranded RNA, which comes from either endogenous DNA transcription or exogenous sources like a virus. This double-stranded RNA is then cleaved by the ATP-dependent...