Particle-mediated delivery of frataxin plasmid to a human sensory neuronal model of Friedreich's ataxia

Czuba-Wojnilowicz, Ewa; Viventi, Serena; Howden, Sara E.; Maksour, Simon; Hulme, Amy E.; Cortez‐Jugo, Christina; Dottori, Mirella; Caruso, Frank

doi:10.1039/c9bm01757g

Cited by 7 publications

(11 citation statements)

References 34 publications

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“…Multilayered particles and capsules were prepared by LbL assembly of PLArg and anionic PSS on spherical silica templates (Figure a). PSS is a highly biocompatible, FDA-approved material for applications in the gastrointestinal tract and has a demonstrated ability to form stable multilayers with PLArg . LbL assembly of PLArg and PSS and subsequent siRNA binding to the terminal PLArg layer were first studied on a planar surface using QCM-D, which confirmed multilayer buildup (Figure S1).…”

Section: Results and Discussionmentioning

confidence: 90%

“…Microcapsules containing PLArg have been previously reported to deliver and release loaded cargo upon degradation by intracellular proteases in vitro. 36,37 Multilayered particles and capsules were prepared by LbL assembly of PLArg and anionic PSS on spherical silica templates (Figure 2a). PSS is a highly biocompatible, FDA-approved material for applications in the gastrointestinal tract and has a demonstrated ability to form stable multilayers with PLArg.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…PLArg is a cationic polypeptide that has been used to enhance the intracellular translocation of various cargoes via a mechanism that resembles the action of arginine-rich HIV-derived transactivator of transcription (Tat), the first identified cell-penetrating peptide. , In addition, nuclear localization signals that transport proteins to the cell nucleus are often arginine-rich, which may provide an additional benefit for the use PLArg for enhanced nuclear translocation of nucleus-bound siRNA. , In this study, PLArg was used in the assembly of multilayered particles and capsules to facilitate complexation with negatively charged siRNA by electrostatic interactions. Microcapsules containing PLArg have been previously reported to deliver and release loaded cargo upon degradation by intracellular proteases in vitro. , …”

Section: Results and Discussionmentioning

confidence: 99%

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Layer-by-Layer Particles Deliver Epigenetic Silencing siRNA to HIV-1 Latent Reservoir Cell Types

Czuba-Wojnilowicz

Klemm²,

Cortez‐Jugo

et al. 2023

Mol. Pharmaceutics

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For over two decades, nanomaterials have been employed to facilitate intracellular delivery of small interfering RNA (siRNA), both in vitro and in vivo, to induce post-transcriptional gene silencing (PTGS) via RNA interference. Besides PTGS, siRNAs are also capable of transcriptional gene silencing (TGS) or epigenetic silencing, which targets the gene promoter in the nucleus and prevents transcription via repressive epigenetic modifications. However, silencing efficiency is hampered by poor intracellular and nuclear delivery. Here, polyarginine-terminated multilayered particles are reported as a versatile system for the delivery of TGS-inducing siRNA to potently suppress virus transcription in HIV-infected cells. siRNA is complexed with multilayered particles formed by layer-by-layer assembly of poly(styrenesulfonate) and poly(arginine) and incubated with HIV-infected cell types, including primary cells. Using deconvolution microscopy, uptake of fluorescently labeled siRNA is observed in the nuclei of HIV-1 infected cells. Viral RNA and protein are measured to confirm functional virus silencing from siRNA delivered using particles 16 days post-treatment. This work extends conventional particle-enabled PTGS siRNA delivery to the TGS pathway and paves the way for future studies on particle-delivered siRNA for efficient TGS of various diseases and infections, including HIV.

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Section: Results and Discussionmentioning

confidence: 90%

Section: ■ Results and Discussionmentioning

confidence: 99%

Section: Results and Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Layer-by-Layer Particles Deliver Epigenetic Silencing siRNA to HIV-1 Latent Reservoir Cell Types

Czuba-Wojnilowicz

Klemm²,

Cortez‐Jugo

et al. 2023

Mol. Pharmaceutics

Self Cite

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“…Recently, repeat-targeted nucleic acids (L. Li et al, 2016 ; Shen et al, 2019 ; Shen et al, 2020) and synthetic transcription elongation factors (Syn-TEFs) ( Erwin et al, 2017 ) were used to elevate FXN expression in FRDA iPSC-based models. In addition, particle-mediated delivery of frataxin-encoding plasmid DNA has been used to increase FXN levels in FRDA iPSC-based sensory neurons ( Czuba-Wojnilowicz et al, 2020 ). Oligonucleotides targeting 5′ and/or 3’ untranslated regions of the FXN transcript increased FXN mRNA and protein levels in FRDA iPSC-based neuronal progenitor cells ( Belbellaa et al, 2020 ).…”

Section: Generation Of Patient-specific Induced Pluripotent Stem Cellsmentioning

confidence: 99%

Perspectives on current models of Friedreich’s ataxia

Kelekçi

Yıldız

Sevinç

et al. 2022

Front. Cell Dev. Biol.

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Friedreich’s ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

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“…found higher particle association of positively charged silica particles compared with negatively charged particles, which might be due to the material itself or difference in the excitability of the cells. [ 69 ] When sensory neurons were organized in a 3D structure in the form of neurospheres, particle size had a more pronounced effect than charge, although charge was found to influence cell binding and internalization. [ 70 ] Both positively charged and negatively charged particles with sizes below 280 nm were found to penetrate deeper into neurospheres than particles >400 nm.…”

Section: Single Cell Levelmentioning

confidence: 99%

A Focus on “Bio” in Bio–Nanoscience: The Impact of Biological Factors on Nanomaterial Interactions

Cortez‐Jugo

Czuba-Wojnilowicz

Tan

et al. 2021

Adv Healthcare Materials

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Bio–nanoscience research encompasses studies on the interactions of nanomaterials with biological structures or what is commonly referred to as the biointerface. Fundamental studies on the influence of nanomaterial properties, including size, shape, composition, and charge, on the interaction with the biointerface have been central in bio–nanoscience to assess nanomaterial efficacy and safety for a range of biomedical applications. However, the state of the cells, tissues, or biological models can also influence the behavior of nanomaterials at the biointerface and their intracellular processing. Focusing on the “bio” in bio–nano, this review discusses the impact of biological properties at the cellular, tissue, and whole organism level that influences nanomaterial behavior, including cell type, cell cycle, tumor physiology, and disease states. Understanding how the biological factors can be addressed or exploited to enhance nanomaterial accumulation and uptake can guide the design of better and suitable models to improve the outcomes of materials in nanomedicine.

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Particle-mediated delivery of frataxin plasmid to a human sensory neuronal model of Friedreich's ataxia

Abstract: Multilayered particles in gene therapy for Friedreich's ataxia induce a 27 000-fold increase in frataxin gene expression in a patient-derived cell model.

Cited by 7 publications

References 34 publications

Layer-by-Layer Particles Deliver Epigenetic Silencing siRNA to HIV-1 Latent Reservoir Cell Types

Layer-by-Layer Particles Deliver Epigenetic Silencing siRNA to HIV-1 Latent Reservoir Cell Types

Perspectives on current models of Friedreich’s ataxia

A Focus on “Bio” in Bio–Nanoscience: The Impact of Biological Factors on Nanomaterial Interactions

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