Submit to Pharmaceutics Review for Pharmaceutics Propose a Special Issue

Journal Menu

Journal Browser

► Journal Browser

Recent Trends in Oligonucleotide Based Therapies

Print Special Issue Flyer
Special Issue Editors
Special Issue Information
Keywords
Benefits of Publishing in a Special Issue
Published Papers

A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Gene and Cell Therapy".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 45169

Share This Special Issue

Special Issue Editors

Dr. Andreia F. Jorge

E-Mail Website
Guest Editor

Coimbra Chemistry Centre (CQC), Department of Chemistry, University of Coimbra, Rua Larga, 3004-535 Coimbra, Portugal
Interests: chemical-modified therapeutic oligonucleotides; antisense oligonucleotides; RNA interference; antiproliferative oligonucleotides; sequence-specific protein–DNA/RNA interactions; lipid- and polymer-based drug delivery systems; programmable self-assembling DNA nanostructures

Dr. Santiago Grijalvo

E-Mail Website
Guest Editor

1. Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain
2. Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Jordi Girona 18-26, E-08034 Barcelona, Spain
Interests: antisense technology; bioconjugation; drug delivery; formulation; nucleic acids chemistry; nucleic acids delivery; polymeric nanoparticles; RNA interference
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Ramon Eritja

E-Mail Website
Guest Editor

1. Institute for Advanced Chemistry of Catalonia (IQAC-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain
2. Networking Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), Jordi Girona 18-26, E-08034 Barcelona, Spain
Interests: siRNA; antisense oligonucleotides; G-quadruplex; DNA triplex; i-motif; DNA nanotechnology; gene silencing; aptamers; drug delivery; DNA; RNA; oligonucleotide synthesis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

In the past few decades, significant efforts have been made towards the clinical application of oligonucleotides, mainly antisense DNA and small interfering RNA, with several already hitting the market. However, the potential of the therapeutic applications of RNA-based strategies have recently been spotlighted after the first approval of mRNA vaccines in response to COVID-19 pandemic. These molecules have the power to tackle targets that are usually considered to be “undruggable” by blocking the translation or transcription of a specific gene by stimulating the degradation of a particular messenger RNA. So far, multiple technologies have been developed to enhance oligonucleotide pharmacokinetics and pharmacodynamics. The most commonly used strategies include chemical modification, conjugation to cell-targeting moieties, and nanoparticle formulation. However, despite all of the progress that has been made, their rapid degradation in biological fluids along with the difficulty of crossing physiological barriers make cell delivery a hard task to achieve, and there is still a need for more competent delivery approaches.

This Special Issue aims to collect reviews, original research articles, and short communications covering innovative strategies in the design, synthesis, and characterization of therapeutic oligonucleotides as well as advances in their delivery based on nanotechnologies. Research concerning the study of sequence-specific protein–DNA/RNA interactions will be also considered.

We are pleased to invite you to contribute your valuable research to this Special Issue on “Recent trends in oligonucleotide based therapies”.

Dr. Andreia F. Jorge
Prof. Dr. Ramon Eritja
Dr. Santiago Grijalvo
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceutics is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

• gene therapy
• nanomedicine
• oligonucleotide delivery systems
• chemical-modified oligonucleotices
• oligonucleotide conjugates
• antisense oligonucleotides
• RNA interference
• anti-miRNA oligonucleotides
• aptamers
• protein–DNA/RNA interactions.

Benefits of Publishing in a Special Issue

Ease of navigation: Grouping papers by topic helps scholars navigate broad scope journals more efficiently.
Greater discoverability: Special Issues support the reach and impact of scientific research. Articles in Special Issues are more discoverable and cited more frequently.
Expansion of research network: Special Issues facilitate connections among authors, fostering scientific collaborations.
External promotion: Articles in Special Issues are often promoted through the journal's social media, increasing their visibility.
Reprint: MDPI Books provides the opportunity to republish successful Special Issues in book format, both online and in print.

Further information on MDPI's Special Issue policies can be found here.

Published Papers (13 papers)

Download All Papers

Order results

Result details

Show export options Show export options

Select all

Export citation of selected articles as:

Research

Jump to: Review

13 pages, 2129 KiB

Open AccessArticle

Ensemble-Learning and Feature Selection Techniques for Enhanced Antisense Oligonucleotide Efficacy Prediction in Exon Skipping

by Alex Zhu, Shuntaro Chiba, Yuki Shimizu, Katsuhiko Kunitake, Yasushi Okuno, Yoshitsugu Aoki and Toshifumi Yokota

Pharmaceutics 2023, 15(7), 1808; https://doi.org/10.3390/pharmaceutics15071808 - 24 Jun 2023

Cited by 2 | Viewed by 3906

Abstract

Antisense oligonucleotide (ASO)-mediated exon skipping has become a valuable tool for investigating gene function and developing gene therapy. Machine-learning-based computational methods, such as eSkip-Finder, have been developed to predict the efficacy of ASOs via exon skipping. However, these methods are computationally demanding, and the accuracy of predictions remains suboptimal. In this study, we propose a new approach to reduce the computational burden and improve the prediction performance by using feature selection within machine-learning algorithms and ensemble-learning techniques. We evaluated our approach using a dataset of experimentally validated exon-skipping events, dividing it into training and testing sets. Our results demonstrate that using a three-way-voting approach with random forest, gradient boosting, and XGBoost can significantly reduce the computation time to under ten seconds while improving prediction performance, as measured by R² for both 2′-O-methyl nucleotides (2OMe) and phosphorodiamidate morpholino oligomers (PMOs). Additionally, the feature importance ranking derived from our approach is in good agreement with previously published results. Our findings suggest that our approach has the potential to enhance the accuracy and efficiency of predicting ASO efficacy via exon skipping. It could also facilitate the development of novel therapeutic strategies. This study could contribute to the ongoing efforts to improve ASO design and optimize gene therapy approaches. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

22 pages, 5483 KiB

Open AccessArticle

BlockmiR AONs as Site-Specific Therapeutic MBNL Modulation in Myotonic Dystrophy 2D and 3D Muscle Cells and HSA^LR Mice

by Sarah J. Overby, Estefanía Cerro-Herreros, Jorge Espinosa-Espinosa, Irene González-Martínez, Nerea Moreno, Juan M. Fernández-Costa, Jordina Balaguer-Trias, Javier Ramón-Azcón, Manuel Pérez-Alonso, Thorleif Møller, Beatriz Llamusí and Rubén Artero

Pharmaceutics 2023, 15(4), 1118; https://doi.org/10.3390/pharmaceutics15041118 - 31 Mar 2023

Cited by 4 | Viewed by 3369

Abstract

The symptoms of Myotonic Dystrophy Type 1 (DM1) are multi-systemic and life-threatening. The neuromuscular disorder is rooted in a non-coding CTG microsatellite expansion in the DM1 protein kinase (DMPK) gene that, upon transcription, physically sequesters the Muscleblind-like (MBNL) family of splicing regulator proteins. The high-affinity binding occurring between the proteins and the repetitions disallow MBNL proteins from performing their post-transcriptional splicing regulation leading to downstream molecular effects directly related to disease symptoms such as myotonia and muscle weakness. In this study, we build on previously demonstrated evidence showing that the silencing of miRNA-23b and miRNA-218 can increase MBNL1 protein in DM1 cells and mice. Here, we use blockmiR antisense technology in DM1 muscle cells, 3D mouse-derived muscle tissue, and in vivo mice to block the binding sites of these microRNAs in order to increase MBNL translation into protein without binding to microRNAs. The blockmiRs show therapeutic effects with the rescue of mis-splicing, MBNL subcellular localization, and highly specific transcriptomic expression. The blockmiRs are well tolerated in 3D mouse skeletal tissue inducing no immune response. In vivo, a candidate blockmiR also increases Mbnl1/2 protein and rescues grip strength, splicing, and histological phenotypes. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Graphical abstract

19 pages, 5298 KiB

Open AccessArticle

Effects of Dendrimer-microRNA Nanoformulations against Glioblastoma Stem Cells

by Nadezhda Knauer, Mariya Meschaninova, Sajjad Muhammad, Daniel Hänggi, Jean-Pierre Majoral, Ulf Dietrich Kahlert, Vladimir Kozlov and Evgeny K. Apartsin

Pharmaceutics 2023, 15(3), 968; https://doi.org/10.3390/pharmaceutics15030968 - 17 Mar 2023

Cited by 9 | Viewed by 2261

Abstract

Glioblastoma is a rapidly progressing tumor quite resistant to conventional treatment. These features are currently assigned to a self-sustaining population of glioblastoma stem cells. Anti-tumor stem cell therapy calls for a new means of treatment. In particular, microRNA-based treatment is a solution, which in turn requires specific carriers for intracellular delivery of functional oligonucleotides. Herein, we report a preclinical in vitro validation of antitumor activity of nanoformulations containing antitumor microRNA miR-34a and microRNA-21 synthetic inhibitor and polycationic phosphorus and carbosilane dendrimers. The testing was carried out in a panel of glioblastoma and glioma cell lines, glioblastoma stem-like cells and induced pluripotent stem cells. We have shown dendrimer-microRNA nanoformulations to induce cell death in a controllable manner, with cytotoxic effects being more pronounced in tumor cells than in non-tumor stem cells. Furthermore, nanoformulations affected the expression of proteins responsible for interactions between the tumor and its immune microenvironment: surface markers (PD-L1, TIM3, CD47) and IL-10. Our findings evidence the potential of dendrimer-based therapeutic constructions for the anti-tumor stem cell therapy worth further investigation. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

10 pages, 2221 KiB

Open AccessArticle

The Regioselective Conjugation of the 15-nt Thrombin Aptamer with an Optimized Tripeptide Sequence Greatly Increases the Anticoagulant Activity of the Aptamer

by Irina V. Varizhuk, Vladimir B. Tsvetkov, Ilya Yu. Toropygin, Andrey A. Stomakhin, Natalia A. Kolganova, Sergei A. Surzhikov and Edward N. Timofeev

Pharmaceutics 2023, 15(2), 604; https://doi.org/10.3390/pharmaceutics15020604 - 10 Feb 2023

Cited by 1 | Viewed by 2140

Abstract

Currently, oligonucleotide therapy has emerged as a new paradigm in the treatment of human diseases. In many cases, however, therapeutic oligonucleotides cannot be used directly without modification. Chemical modification or the conjugation of therapeutic oligonucleotides is required to increase their stability or specificity, improve their affinity or inhibitory characteristics, and address delivery issues. Recently, we proposed a conjugation strategy for a 15-nt G-quadruplex thrombin aptamer aimed at extending the recognition interface of the aptamer. In particular, we have prepared a series of designer peptide conjugates of the thrombin aptamer, showing improved anticoagulant activity. Herein, we report a new series of aptamer–peptide conjugates with optimized peptide sequences. The anti-thrombotic activity of aptamer conjugates was notably improved. The lead conjugate, TBA–GLE, was able to inhibit thrombin-induced coagulation approximately six-fold more efficiently than the unmodified aptamer. In terms of its anticoagulant activity, the TBA–GLE conjugate approaches NU172, one of the most potent G-quadruplex thrombin aptamers. Molecular dynamics studies have confirmed that the principles applied to the design of the peptide side chain are efficient instruments for improving aptamer characteristics for the proposed TBA conjugate model. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

19 pages, 4762 KiB

Open AccessArticle

Cyclodextrin-Based Nanoparticles for Delivery of Antisense Oligonucleotides Targeting Huntingtin

by Monique C. P. Mendonça, Yao Sun, Michael F. Cronin, Andrew J. Lindsay, John F. Cryan and Caitriona M. O’Driscoll

Pharmaceutics 2023, 15(2), 520; https://doi.org/10.3390/pharmaceutics15020520 - 3 Feb 2023

Cited by 11 | Viewed by 3880

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. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Graphical abstract

16 pages, 3989 KiB

Open AccessArticle

Trioleyl Pyridinium, a Cationic Transfection Agent for the Lipofection of Therapeutic Oligonucleotides into Mammalian Cells

by Ana Delgado, Rosa Griera, Núria Llor, Ester López-Aguilar, Maria Antònia Busquets, Véronique Noé and Carlos J. Ciudad

Pharmaceutics 2023, 15(2), 420; https://doi.org/10.3390/pharmaceutics15020420 - 27 Jan 2023

Cited by 2 | Viewed by 2098

Abstract

Background: One of the most significant limitations that therapeutic oligonucleotides present is the development of specific and efficient delivery vectors for the internalization of nucleic acids into cells. Therefore, there is a need for the development of new transfection agents that ensure a proper and efficient delivery into mammalian cells. Methods: We describe the synthesis of 1,3,5-tris[(4-oelyl-1-pyridinio)methyl]benzene tribromide (TROPY) and proceeded to the validation of its binding capacity toward oligonucleotides, the internalization of DNA into the cells, the effect on cell viability, apoptosis, and its capability to transfect plasmid DNA. Results: The synthesis and chemical characterization of TROPY, which can bind DNA and transfect oligonucleotides into mammalian cells through clathrin and caveolin-mediated endocytosis, are described. Using a PPRH against the antiapoptotic survivin gene as a model, we validated that the complex TROPY–PPRH decreased cell viability in human cancer cells, increased apoptosis, and reduced survivin mRNA and protein levels. TROPY was also able to stably transfect plasmid DNA, as demonstrated by the formation of viable colonies upon the transfection of a dhfr minigene into dhfr-negative cells and the subsequent metabolic selection. Conclusions: TROPY is an efficient transfecting agent that allows the delivery of therapeutic oligonucleotides, such as PPRHs and plasmid DNA, inside mammalian cells. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

16 pages, 1399 KiB

Open AccessArticle

Improved Metal-Free Approach for the Synthesis of Protected Thiol Containing Thymidine Nucleoside Phosphoramidite and Its Application for the Synthesis of Ligatable Oligonucleotide Conjugates

by Zoltán Kupihár, Györgyi Ferenc, Vencel L. Petrovicz, Viktória R. Fáy, Lajos Kovács, Tamás A. Martinek and Zsófia Hegedüs

Pharmaceutics 2023, 15(1), 248; https://doi.org/10.3390/pharmaceutics15010248 - 11 Jan 2023

Viewed by 2668

Abstract

Oligonucleotide conjugates are versatile scaffolds that can be applied in DNA-based screening platforms and ligand display or as therapeutics. Several different chemical approaches are available for functionalizing oligonucleotides, which are often carried out on the 5′ or 3′ end. Modifying oligonucleotides in the middle of the sequence opens the possibility to ligate the conjugates and create DNA strands bearing multiple different ligands. Our goal was to establish a complete workflow that can be applied for such purposes from monomer synthesis to templated ligation. To achieve this, a monomer is required with an orthogonal functional group that can be incorporated internally into the oligonucleotide sequence. This is followed by conjugation with different molecules and ligation with the help of a complementary template. Here, we show the synthesis and the application of a thiol-modified thymidine nucleoside phosphoramidite to prepare ligatable oligonucleotide conjugates. The conjugations were performed both in solution and on solid phase, resulting in conjugates that can be assembled into multivalent oligonucleotides decorated with tissue-targeting peptides using templated ligation. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

6 pages, 227 KiB

Open AccessCommunication

Smad7 Antisense Oligonucleotide in Crohn’s Disease: A Re-Evaluation and Explanation for the Discordant Results of Clinical Trials

by Giovanni Monteleone and Carmine Stolfi

Pharmaceutics 2023, 15(1), 95; https://doi.org/10.3390/pharmaceutics15010095 - 28 Dec 2022

Cited by 2 | Viewed by 2280

Abstract

In Crohn’s disease (CD) and ulcerative colitis (UC), the major inflammatory bowel diseases (IBD) in human beings, the tissue-damaging inflammatory response is characterized by elevated levels of Suppressor of Mothers Against Decapentaplegic (Smad)7, an inhibitor of the immunosuppressive cytokine Transforming Growth Factor (TGF)-β1. Consistently, preclinical work in mouse models of IBD-like colitis showed that the knockdown of Smad7 with an antisense oligonucleotide (AS) attenuated the mucosal inflammation, thus paving the way for the development of an AS-containing pharmaceutical compound, named mongersen, for clinical use. The initial phase 1 and phase 2 studies showed that oral administration of mongersen was safe and effective in inducing clinical remission in active CD patients. However, subsequently, a large multicentered, randomized, double-blind, placebo-controlled, phase 3 trial was prematurely discontinued because of an interim analysis showing no effect of mongersen on the activity of CD. In this study we will discuss recent data showing that the majority of the batches of mongersen used in the phase 3 study were chemically different from those used in the previous clinical trials, with some of them being unable to knockdown Smad7 in cultured cells. The accumulating evidence highlights the need to maintain consistent manufacturing requirements for clinical AS, as well as the potential benefits of in vitro bioassays as a part of quality control. New clinical trials evaluating mongersen’s impact on IBD using chemically homogenous batches will be needed to ascertain the therapeutic efficacy of such a drug. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Graphical abstract

27 pages, 6473 KiB

Open AccessArticle

Complexation of Oligo- and Polynucleotides with Methoxyphenyl-Functionalized Imidazolium Surfactants

by Darya A. Kuznetsova, Denis M. Kuznetsov, Leysan A. Vasileva, Syumbelya K. Amerhanova, Dilyara N. Valeeva, Diana V. Salakhieva, Viktoriia A. Nikolaeva, Irek R. Nizameev, Daut R. Islamov, Konstantin S. Usachev, Alexandra D. Voloshina and Lucia Ya. Zakharova

Pharmaceutics 2022, 14(12), 2685; https://doi.org/10.3390/pharmaceutics14122685 - 1 Dec 2022

Cited by 10 | Viewed by 2222

Abstract

Interaction between cationic surfactants and nucleic acids attracts much attention due to the possibility of using such systems for gene delivery. Herein, the lipoplexes based on cationic surfactants with imidazolium head group bearing methoxyphenyl fragment (MPI-n, n = 10, 12, 14, 16) and nucleic acids (oligonucleotide and plasmid DNA) were explored. The complex formation was confirmed by dynamic/electrophoretic light scattering, transmission electron microscopy, fluorescence spectroscopy, circular dichroism, and gel electrophoresis. The nanosized lipoplex formation (of about 100–200 nm), contributed by electrostatic, hydrophobic interactions, and intercalation mechanism, has been shown. Significant effects of the hydrocarbon tail length of surfactant and the type of nucleic acid on their interaction was revealed. The cytotoxic effect and transfection ability of lipoplexes studied were determined using M-HeLa, A549 cancer cell lines, and normal Chang liver cells. A selective reduced cytotoxic effect of the complexes on M-HeLa cancer cells was established, as well as a high ability of the systems to be transfected into cancer cells. MPI-n/DNA complexes showed a pronounced transfection activity equal to the commercial preparation Lipofectamine 3000. Thus, it has been shown that MPI-n surfactants are effective agents for nucleic acid condensation and can be considered as potential non-viral vectors for gene delivery. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Graphical abstract

Review

Jump to: Research

16 pages, 1235 KiB

Open AccessReview

Progress in circRNA-Targeted Therapy in Experimental Parkinson’s Disease

by Simoneide Souza Titze-de-Almeida and Ricardo Titze-de-Almeida

Pharmaceutics 2023, 15(8), 2035; https://doi.org/10.3390/pharmaceutics15082035 - 28 Jul 2023

Cited by 9 | Viewed by 2223

Abstract

Circular RNAs (circRNAs) are single-stranded RNA molecules often circularized by backsplicing. Growing evidence implicates circRNAs in the underlying mechanisms of various diseases, such as Alzheimer’s and Parkinson’s disease (PD)—the first and second most prevalent neurodegenerative disorders. In this sense, circSNCA, circHIPK2, circHIPK3, and circSLC8A1 are circRNAs that have been related to the neurodegenerative process of PD. Gain-of-function and loss-of-function studies on circRNAs have shed light on their roles in the pathobiology of various diseases. Gain-of-function approaches typically employ viral or non-viral vectors that hyperexpress RNA sequences capable of circularizing to form the specific circRNA under investigation. In contrast, loss-of-function studies utilize CRISPR/Cas systems, antisense oligonucleotides (ASOs), or RNAi techniques to knock down the target circRNA. The role of aberrantly expressed circRNAs in brain pathology has raised a critical question: could circRNAs serve as viable targets for neuroprotective treatments? Translating any oligonucleotide-based therapy, including those targeting circRNAs, involves developing adequate brain delivery systems, minimizing off-target effects, and addressing the high costs of treatment. Nonetheless, RNAi-based FDA-approved drugs have entered the market, and circRNAs have attracted significant attention and investment from major pharmaceutical companies. Spanning from bench to bedside, circRNAs present a vast opportunity in biotechnology for oligonucleotide-based therapies designed to slow or even halt the progression of neurodegenerative diseases. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

12 pages, 541 KiB

Open AccessReview

Recent Trends in Antisense Therapies for Duchenne Muscular Dystrophy

by Harry Wilton-Clark and Toshifumi Yokota

Pharmaceutics 2023, 15(3), 778; https://doi.org/10.3390/pharmaceutics15030778 - 26 Feb 2023

Cited by 32 | Viewed by 5126

Abstract

Duchenne muscular dystrophy (DMD) is a debilitating and fatal genetic disease affecting 1/5000 boys globally, characterized by progressive muscle breakdown and eventual death, with an average lifespan in the mid–late twenties. While no cure yet exists for DMD, gene and antisense therapies have been heavily explored in recent years to better treat this disease. Four antisense therapies have received conditional FDA approval, and many more exist in varying stages of clinical trials. These upcoming therapies often utilize novel drug chemistries to address limitations of existing therapies, and their development could herald the next generation of antisense therapy. This review article aims to summarize the current state of development for antisense-based therapies for the treatment of Duchenne muscular dystrophy, exploring candidates designed for both exon skipping and gene knockdown. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Figure 1

25 pages, 3749 KiB

Open AccessReview

Lipid and Peptide-Oligonucleotide Conjugates for Therapeutic Purposes: From Simple Hybrids to Complex Multifunctional Assemblies

by Carme Fàbrega, Anna Aviñó, Natalia Navarro, Andreia F. Jorge, Santiago Grijalvo and Ramon Eritja

Pharmaceutics 2023, 15(2), 320; https://doi.org/10.3390/pharmaceutics15020320 - 18 Jan 2023

Cited by 18 | Viewed by 7822

Abstract

Antisense and small interfering RNA (siRNA) oligonucleotides have been recognized as powerful therapeutic compounds for targeting mRNAs and inducing their degradation. However, a major obstacle is that unmodified oligonucleotides are not readily taken up into tissues and are susceptible to degradation by nucleases. For these reasons, the design and preparation of modified DNA/RNA derivatives with better stability and an ability to be produced at large scale with enhanced uptake properties is of vital importance to improve current limitations. In the present study, we review the conjugation of oligonucleotides with lipids and peptides in order to produce oligonucleotide conjugates for therapeutics aiming to develop novel compounds with favorable pharmacokinetics. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Graphical abstract

19 pages, 1718 KiB

Open AccessReview

Oligonucleotide Therapeutics for Age-Related Musculoskeletal Disorders: Successes and Challenges

by Thomas A. Nicholson, Michael Sagmeister, Susanne N. Wijesinghe, Hussein Farah, Rowan S. Hardy and Simon W. Jones

Pharmaceutics 2023, 15(1), 237; https://doi.org/10.3390/pharmaceutics15010237 - 10 Jan 2023

Cited by 3 | Viewed by 3480

Abstract

Age-related disorders of the musculoskeletal system including sarcopenia, osteoporosis and arthritis represent some of the most common chronic conditions worldwide, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. Collectively, these conditions involve multiple tissues, including skeletal muscle, bone, articular cartilage and the synovium within the joint lining. In this review, we discuss the potential for oligonucleotide therapies to combat the unmet clinical need in musculoskeletal disorders by evaluating the successes of oligonucleotides to modify candidate pathological gene targets and cellular processes in relevant tissues and cells of the musculoskeletal system. Further, we discuss the challenges that remain for the clinical development of oligonucleotides therapies for musculoskeletal disorders and evaluate some of the current approaches to overcome these. Full article

(This article belongs to the Special Issue Recent Trends in Oligonucleotide Based Therapies)

► Show Figures

Journal Menu

Journal Browser

Recent Trends in Oligonucleotide Based Therapies

Share This Special Issue

Special Issue Editors

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (13 papers)

Research

Review

Further Information

Guidelines

MDPI Initiatives

Follow MDPI