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Updated: Aug 8, 2025
Fractionation for Resolution of Soluble and Insoluble Huntingtin Species
Published on: February 27, 2018
Cyclodextrin-Based Nanoparticles for Delivery of Antisense Oligonucleotides Targeting Huntingtin
Monique C P Mendonça1, Yao Sun1, Michael F Cronin1
1Phamacodelivery Group, School of Pharmacy, University College Cork, T12 YT20 Cork, Ireland.
Insights
Modified cyclodextrin nanoparticles effectively deliver antisense oligonucleotides to lower mutant huntingtin (mHTT) protein levels, offering a promising strategy for Huntington's disease (HD) treatment.
Area of Science:
- Neuroscience
- Genetics
- Nanotechnology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the huntingtin gene, leading to mutant huntingtin (mHTT) protein accumulation.
- Current antisense oligonucleotide (ASO) therapies show potential but face challenges in sustained mHTT silencing and effective delivery.
Purpose of the Study:
- To evaluate cyclodextrin-based nanoparticles (CDs) as a delivery platform for ASOs targeting HTT in Huntington's disease.
- To compare the efficacy of three distinct CD structures for ASO delivery and mHTT downregulation.
Main Methods:
- Designed and synthesized three cyclodextrin nanoparticles (CDs) with varying chemical structures.
- Tested CD-ASO complexes in striatal neurons and patient-derived fibroblasts for mHTT downregulation.
- Incorporated a brain-targeting peptide (RVG) into modified gamma-CDs and assessed efficacy using an in vitro blood-brain barrier model.
Main Results:
- Modified gamma-CDs demonstrated superior uptake efficiency and significant downregulation of mHTT at both protein and allele levels.
- RVG-modified gamma-CDs enhanced mHTT protein and HD-causing allele SNP1 downregulation compared to untargeted CDs.
- The ASO-CD strategy showed potential for allele-specific mHTT reduction, an added benefit to the non-allele-specific ASO sequence.
Conclusions:
- Cyclodextrin nanoparticles represent a feasible platform for delivering ASO therapeutics for Huntington's disease.
- Modified gamma-CDs, particularly with brain-targeting peptides, show promise for improving ASO delivery and efficacy in HD treatment.
- This approach offers a potential strategy to overcome delivery challenges and achieve sustained mHTT lowering.
Abstract:
Huntington's disease (HD) is a progressive inherited neurodegenerative disease caused by a CAG repeat expansion in the huntingtin gene, which is translated into the pathologic mutant huntingtin (mHTT) protein. Despite the great potential of HTT lowering strategies and the numerous antisense oligonucleotides (ASOs) in pre- and clinical trials, sustained silencing of mHTT has not been achieved. As a strategy to improve ASO delivery, cyclodextrin-based nanoparticles (CDs) offer a promising approach. Here, three CDs with distinct chemical structures were designed and their efficacies were compared as potential platforms for the delivery of ASO targeting HTT. Results using striatal neurons and HD patient-derived fibroblasts indicate that modified γ-CDs exhibited the best uptake efficiency and successfully downregulated mHTT at protein and allele levels. The incorporation of the brain-targeting peptide RVG into the modified γ-CDs showed greater downregulation of mHTT protein and HD-causing allele SNP1 than untargeted ones in an in vitro blood-brain barrier model. Although the ASO sequence was designed as a nonallele-specific therapeutic approach, our strategy gives an additional benefit of some mHTT selectivity. Overall, this study demonstrated the CD platform's feasibility for delivering ASO-based therapeutics for HD treatment.
