Biomedicines

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Open AccessEditorial

Oligonucleotides-Based Therapeutics

by Bernard Lebleu

Biomedicines 2021, 9(10), 1355; https://doi.org/10.3390/biomedicines9101355 - 29 Sep 2021

Cited by 1 | Viewed by 1742

Abstract

This Special Issue of Biomedicines aims to outline nucleic-acid-based strategies that have emerged as tools to regulate specific gene expression and, more recently, as a new class of medicines [...] Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

Research

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17 pages, 2570 KiB

Open AccessArticle

Novel Orthogonally Hydrocarbon-Modified Cell-Penetrating Peptide Nanoparticles Mediate Efficient Delivery of Splice-Switching Antisense Oligonucleotides In Vitro and In Vivo

by Safa Bazaz, Tõnis Lehto, Rahel Tops, Olof Gissberg, Dhanu Gupta, Burcu Bestas, Jeremy Bost, Oscar P. B. Wiklander, Helena Sork, Eman M. Zaghloul, Doste R. Mamand, Mattias Hällbrink, Rannar Sillard, Osama Saher, Kariem Ezzat, C. I. Edvard Smith, Samir EL Andaloussi and Taavi Lehto

Biomedicines 2021, 9(8), 1046; https://doi.org/10.3390/biomedicines9081046 - 19 Aug 2021

Cited by 6 | Viewed by 3507

Abstract

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) [...] Read more.

Splice-switching therapy with splice-switching oligonucleotides (SSOs) has recently proven to be a clinically applicable strategy for the treatment of several mis-splice disorders. Despite this, wider application of SSOs is severely limited by the inherently poor bioavailability of SSO-based therapeutic compounds. Cell-penetrating peptides (CPPs) are a class of drug delivery systems (DDSs) that have recently gained considerable attention for improving the uptake of various oligonucleotide (ON)-based compounds, including SSOs. One strategy that has been successfully applied to develop effective CPP vectors is the introduction of various lipid modifications into the peptide. Here, we repurpose hydrocarbon-modified amino acids used in peptide stapling for the orthogonal introduction of hydrophobic modifications into the CPP structure during peptide synthesis. Our data show that α,α-disubstituted alkenyl-alanines can be successfully utilized to introduce hydrophobic modifications into CPPs to improve their ability to formulate SSOs into nanoparticles (NPs), and to mediate high delivery efficacy and tolerability both in vitro and in vivo. Conclusively, our results offer a new flexible approach for the sequence-specific introduction of hydrophobicity into the structure of CPPs and for improving their delivery properties. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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18 pages, 3869 KiB

Open AccessArticle

Antisense Oligonucleotide-Based Therapeutic against Menin for Triple-Negative Breast Cancer Treatment

by Dang Tan Nguyen, Thi Khanh Le, Clément Paris, Chaïma Cherif, Stéphane Audebert, Sandra Oluchi Udu-Ituma, Sébastien Benizri, Philippe Barthélémy, François Bertucci, David Taïeb and Palma Rocchi

Biomedicines 2021, 9(7), 795; https://doi.org/10.3390/biomedicines9070795 - 8 Jul 2021

Cited by 9 | Viewed by 3687

Abstract

The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human [...] Read more.

The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2) and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer; however, the functions of menin in TNBC remain unknown. Here, we have demonstrated that menin is expressed in various TNBC subtypes with the strongest expression in the TNBC Hs 578T cells. The depletion of menin by an antisense oligonucleotide (ASO) inhibits cell proliferation, enhances apoptosis in Hs 578T cells, highlighting the oncogenic functions of menin in this TNBC model. ASO-based menin silencing also delays the tumor progression of TNBC xenografts. Analysis of the menin interactome suggests that menin could drive TNBC tumorigenesis through the regulation of MLL/KMT2A-driven transcriptional activity, mRNA 3′-end processing and apoptosis. The study provides a rationale behind the use of ASO-based therapy, targeting menin in monotherapy or in combination with chemo or PARP inhibitors for menin-positive TNBC treatments. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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15 pages, 2259 KiB

Open AccessArticle

Targeted SMN Exon Skipping: A Useful Control to Assess In Vitro and In Vivo Splice-Switching Studies

by Loren L. Flynn, Chalermchai Mitrpant, Abbie Adams, Ianthe L. Pitout, Anja Stirnweiss, Sue Fletcher and Steve D. Wilton

Biomedicines 2021, 9(5), 552; https://doi.org/10.3390/biomedicines9050552 - 14 May 2021

Cited by 7 | Viewed by 3379

Abstract

The literature surrounding the use of antisense oligonucleotides continues to grow, with new disease and mechanistic applications constantly evolving. Furthermore, the discovery and advancement of novel chemistries continues to improve antisense delivery, stability and effectiveness. For each new application, a rational sequence design [...] Read more.

The literature surrounding the use of antisense oligonucleotides continues to grow, with new disease and mechanistic applications constantly evolving. Furthermore, the discovery and advancement of novel chemistries continues to improve antisense delivery, stability and effectiveness. For each new application, a rational sequence design is recommended for each oligomer, as is chemistry and delivery optimization. To confirm oligomer delivery and antisense activity, a positive control AO sequence with well characterized target-specific effects is recommended. Here, we describe splice-switching antisense oligomer sequences targeting the ubiquitously expressed human and mouse SMN and Smn genes for use as control AOs for this purpose. We report two AO sequences that induce targeted skipping of SMN1/SMN2 exon 7 and two sequences targeting the Smn gene, that induce skipping of exon 5 and exon 7. These antisense sequences proved effective in inducing alternative splicing in both in vitro and in vivo models and are therefore broadly applicable as controls. Not surprisingly, we discovered a number of differences in efficiency of exon removal between the two species, further highlighting the differences in splice regulation between species. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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15 pages, 3430 KiB

Open AccessArticle

Targeting of the Essential acpP, ftsZ, and rne Genes in Carbapenem-Resistant Acinetobacter baumannii by Antisense PNA Precision Antibacterials

by Alireza Japoni Nejad, Nader Shahrokhi and Peter E. Nielsen

Biomedicines 2021, 9(4), 429; https://doi.org/10.3390/biomedicines9040429 - 15 Apr 2021

Cited by 16 | Viewed by 3266

Abstract

Infections by carbapenem-resistant A. baumannii (CRAB), a widespread nosocomial pathogen, are becoming increasingly difficult to prevent and treat. Therefore, there is an urgent need for discovery of novel antibiotics against CRAB. Programmable, precision antisense antibiotics, e.g., based on the nucleic acid mimic PNA [...] Read more.

Infections by carbapenem-resistant A. baumannii (CRAB), a widespread nosocomial pathogen, are becoming increasingly difficult to prevent and treat. Therefore, there is an urgent need for discovery of novel antibiotics against CRAB. Programmable, precision antisense antibiotics, e.g., based on the nucleic acid mimic PNA (peptide nucleic acid) have shown promise in this respect in the form of PNA-BPP (bacteria penetrating peptide) conjugates targeting essential bacterial genes. In the present study, we designed and synthesized a series of PNA-BPPs targeting the translation initiation region of the ftsZ, acpP, or rne gene of CRAB strains. The antimicrobial activity of the compounds and effects on gene expression level was compared to that of analogous mismatch PNA controls. Three antisense conjugates (KFF)₃K-eg1-(acpP)PNA (5639), (KFF)₃K-eg1-(ftsZ)PNA (5612), and (KFF)₃-K-eg1-(rne)PNA (5656) exhibited complete growth inhibition against several CRAB strains at 1–2, 2–8, and 2 µM, respectively, and the compounds were bactericidal at 1–2× MIC. The bactericidal effect was correlated to reduction of target gene mRNA level using RT-qPCR, and the compounds showed no bacterial membrane disruption activity at 1–2× MIC. PNA5612 was tested against a series of 12 CRAB isolates and all were sensitive at 2–8 µM. In addition, the conjugates exhibited no cellular toxicity in the HepG2 cell line (up to 20 μM) and did not shown significant antibacterial activity against other Gram negatives (E. coli, P. aeruginosa). These results provide a starting point for discovery of antisense precision designer antibiotics for specific treatment of CRAB infections. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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15 pages, 3596 KiB

Open AccessArticle

Inhibitory Effects of STAT3 Transcription Factor by Synthetic Decoy ODNs on Autophagy in Renal Fibrosis

by Young-Ah Kim, Hyun-Ju Kim, Mi-Gyeong Gwon, Hyemin Gu, Hyun-Jin An, Seongjae Bae, Jaechan Leem, Hyun Jin Jung and Kwan-Kyu Park

Biomedicines 2021, 9(4), 331; https://doi.org/10.3390/biomedicines9040331 - 25 Mar 2021

Cited by 8 | Viewed by 2924

Abstract

Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal [...] Read more.

Autophagy in the proximal tubules may promote fibrosis by activating tubular cell death, interstitial inflammation, and the production of pro-fibrotic factors. The signal transducer and activator of transcription 3 (STAT3) is activated as a potential transcription factor, which mediates the stimulation of renal fibrosis. We investigated the role of the STAT3 in autophagy and its effect on the prevention of interstitial renal fibrosis. In this study, we use synthesized STAT3 decoy oligonucleotides (ODN), which were injected into the tail veins of unilateral ureteral obstruction (UUO) mice, to explore the regulation of autophagy in UUO-induced renal fibrosis. The expression of interleukin-6 (IL-6), interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and collagen were decreased by STAT3 decoy ODN. The autophagy markers microtubule-associated protein light chain 3 (LC3) and fibronectin, were identified through immunofluorescent staining, indicating that they were reduced in the group injected with ODN. The expressions of LC3, Beclin1, p62, and autophagy-related 5–12 (Atg5–12) and hypoxia inducible factor-1α (HIF-1α) were inhibited in the ODN injection group. We determined the inhibitory effect of autophagy in chronic kidney disease and confirmed that STAT3 decoy ODN effectively inhibited autophagy by inhibiting the expression of STAT3 transcription factors in the UUO group. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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Review

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17 pages, 904 KiB

Open AccessReview

Oligonucleotide Therapies in the Treatment of Arthritis: A Narrative Review

by Susanne N. Wijesinghe, Mark A. Lindsay and Simon W. Jones

Biomedicines 2021, 9(8), 902; https://doi.org/10.3390/biomedicines9080902 - 27 Jul 2021

Cited by 12 | Viewed by 3080

Abstract

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common chronic inflammatory joint diseases, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. The pathology of both OA and RA involves multiple tissues within [...] Read more.

Osteoarthritis (OA) and rheumatoid arthritis (RA) are two of the most common chronic inflammatory joint diseases, for which there remains a great clinical need to develop safer and more efficacious pharmacological treatments. The pathology of both OA and RA involves multiple tissues within the joint, including the synovial joint lining and the bone, as well as the articular cartilage in OA. In this review, we discuss the potential for the development of oligonucleotide therapies for these disorders by examining the evidence that oligonucleotides can modulate the key cellular pathways that drive the pathology of the inflammatory diseased joint pathology, as well as evidence in preclinical in vivo models that oligonucleotides can modify disease progression. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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27 pages, 1913 KiB

Open AccessReview

Peptide-Based Nanoparticles for Therapeutic Nucleic Acid Delivery

by Prisca Boisguérin, Karidia Konate, Emilie Josse, Eric Vivès and Sébastien Deshayes

Biomedicines 2021, 9(5), 583; https://doi.org/10.3390/biomedicines9050583 - 20 May 2021

Cited by 39 | Viewed by 7429

Abstract

Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage [...] Read more.

Gene therapy offers the possibility to skip, repair, or silence faulty genes or to stimulate the immune system to fight against disease by delivering therapeutic nucleic acids (NAs) to a patient. Compared to other drugs or protein treatments, NA-based therapies have the advantage of being a more universal approach to designing therapies because of the versatility of NA design. NAs (siRNA, pDNA, or mRNA) have great potential for therapeutic applications for an immense number of indications. However, the delivery of these exogenous NAs is still challenging and requires a specific delivery system. In this context, beside other non-viral vectors, cell-penetrating peptides (CPPs) gain more and more interest as delivery systems by forming a variety of nanocomplexes depending on the formulation conditions and the properties of the used CPPs/NAs. In this review, we attempt to cover the most important biophysical and biological aspects of non-viral peptide-based nanoparticles (PBNs) for therapeutic nucleic acid formulations as a delivery system. The most relevant peptides or peptide families forming PBNs in the presence of NAs described since 2015 will be presented. All these PBNs able to deliver NAs in vitro and in vivo have common features, which are characterized by defined formulation conditions in order to obtain PBNs from 60 nm to 150 nm with a homogeneous dispersity (PdI lower than 0.3) and a positive charge between +10 mV and +40 mV. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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26 pages, 1654 KiB

Open AccessReview

Non-Immunotherapy Application of LNP-mRNA: Maximizing Efficacy and Safety

by Irena Vlatkovic

Biomedicines 2021, 9(5), 530; https://doi.org/10.3390/biomedicines9050530 - 10 May 2021

Cited by 62 | Viewed by 19170

Abstract

Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of [...] Read more.

Lipid nanoparticle (LNP) formulated messenger RNA-based (LNP-mRNA) vaccines came into the spotlight as the first vaccines against SARS-CoV-2 virus to be applied worldwide. Long-known benefits of mRNA-based technologies consisting of relatively simple and fast engineering of mRNA encoding for antigens and proteins of interest, no genomic integration, and fast and efficient manufacturing process compared with other biologics have been verified, thus establishing a basis for a broad range of applications. The intrinsic immunogenicity of LNP formulated in vitro transcribed (IVT) mRNA is beneficial to the LNP-mRNA vaccines. However, avoiding immune activation is critical for therapeutic applications of LNP-mRNA for protein replacement where targeted mRNA expression and repetitive administration of high doses for a lifetime are required. This review summarizes our current understanding of immune activation induced by mRNA, IVT byproducts, and LNP. It gives a comprehensive overview of the present status of preclinical and clinical studies in which LNP-mRNA is used for protein replacement and treatment of rare diseases with an emphasis on safety. Moreover, the review outlines innovations and strategies to advance pharmacology and safety of LNP-mRNA for non-immunotherapy applications. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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12 pages, 578 KiB

Open AccessReview

Chemical Manipulation of the Endosome Trafficking Machinery: Implications for Oligonucleotide Delivery

by Rudolph L. Juliano

Biomedicines 2021, 9(5), 512; https://doi.org/10.3390/biomedicines9050512 - 5 May 2021

Cited by 22 | Viewed by 3983

Abstract

Antisense oligonucleotides (ASOs), siRNA and splice switching oligonucleotides (SSOs) all have immense potential as therapeutic agents, potential that is now being validated as oligonucleotides enter the clinic. However, progress in oligonucleotide-based therapeutics has been limited by the difficulty in delivering these complex molecules [...] Read more.

Antisense oligonucleotides (ASOs), siRNA and splice switching oligonucleotides (SSOs) all have immense potential as therapeutic agents, potential that is now being validated as oligonucleotides enter the clinic. However, progress in oligonucleotide-based therapeutics has been limited by the difficulty in delivering these complex molecules to their sites of action in the cytosol or nucleus of cells within specific tissues. There are two aspects to the delivery problem. The first is that most types of oligonucleotides have poor uptake into non-hepatic tissues. The second is that much of the oligonucleotide that is taken up by cells is entrapped in endosomes where it is pharmacologically inert. It has become increasingly recognized that endosomal trapping is a key constraint on oligonucleotide therapeutics. Thus, many approaches have been devised to address this problem, primarily ones based on various nanoparticle technologies. However, recently an alternative approach has emerged that employs small molecules to manipulate intracellular trafficking processes so as to enhance oligonucleotide actions. This review presents the current status of this chemical biology approach to oligonucleotide delivery and seeks to point out possible paths for future development. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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15 pages, 1472 KiB

Open AccessReview

The Evolution of Antisense Oligonucleotide Chemistry—A Personal Journey

by Sudhir Agrawal

Biomedicines 2021, 9(5), 503; https://doi.org/10.3390/biomedicines9050503 - 3 May 2021

Cited by 18 | Viewed by 4446

Abstract

Over the last four decades, tremendous progress has been made in use of synthetic oligonucleotides as therapeutics. This has been possible largely by introducing chemical modifications to provide drug like properties to oligonucleotides. In this article I have summarized twists and turns on [...] Read more.

Over the last four decades, tremendous progress has been made in use of synthetic oligonucleotides as therapeutics. This has been possible largely by introducing chemical modifications to provide drug like properties to oligonucleotides. In this article I have summarized twists and turns on use of chemical modifications and their road to success and highlight areas of future directions. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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18 pages, 1379 KiB

Open AccessReview

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

by Maria Gagliardi and Ana Tari Ashizawa

Biomedicines 2021, 9(4), 433; https://doi.org/10.3390/biomedicines9040433 - 16 Apr 2021

Cited by 104 | Viewed by 16664

Abstract

Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential [...] Read more.

Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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12 pages, 869 KiB

Open AccessReview

Silencing Antibiotic Resistance with Antisense Oligonucleotides

by Saumya Jani, Maria Soledad Ramirez and Marcelo E. Tolmasky

Biomedicines 2021, 9(4), 416; https://doi.org/10.3390/biomedicines9040416 - 12 Apr 2021

Cited by 16 | Viewed by 4909

Abstract

Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including [...] Read more.

Antisense technologies consist of the utilization of oligonucleotides or oligonucleotide analogs to interfere with undesirable biological processes, commonly through inhibition of expression of selected genes. This field holds a lot of promise for the treatment of a very diverse group of diseases including viral and bacterial infections, genetic disorders, and cancer. To date, drugs approved for utilization in clinics or in clinical trials target diseases other than bacterial infections. Although several groups and companies are working on different strategies, the application of antisense technologies to prokaryotes still lags with respect to those that target other human diseases. In those cases where the focus is on bacterial pathogens, a subset of the research is dedicated to produce antisense compounds that silence or reduce expression of antibiotic resistance genes. Therefore, these compounds will be adjuvants administered with the antibiotic to which they reduce resistance levels. A varied group of oligonucleotide analogs like phosphorothioate or phosphorodiamidate morpholino residues, as well as peptide nucleic acids, locked nucleic acids and bridge nucleic acids, the latter two in gapmer configuration, have been utilized to reduce resistance levels. The major mechanisms of inhibition include eliciting cleavage of the target mRNA by the host’s RNase H or RNase P, and steric hindrance. The different approaches targeting resistance to β-lactams include carbapenems, aminoglycosides, chloramphenicol, macrolides, and fluoroquinolones. The purpose of this short review is to summarize the attempts to develop antisense compounds that inhibit expression of resistance to antibiotics. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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24 pages, 904 KiB

Open AccessReview

Oligonucleotide-Based Therapies for Renal Diseases

by Fernando Cartón-García, Cassondra Jeanette Saande, Daniel Meraviglia-Crivelli, Rafael Aldabe and Fernando Pastor

Biomedicines 2021, 9(3), 303; https://doi.org/10.3390/biomedicines9030303 - 16 Mar 2021

Cited by 13 | Viewed by 4679

Abstract

The global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging [...] Read more.

The global burden of chronic kidney disease (CKD) is increasing every year and represents a great cost for public healthcare systems, as the majority of these diseases are progressive. Therefore, there is an urgent need to develop new therapies. Oligonucleotide-based drugs are emerging as novel and promising alternatives to traditional drugs. Their expansion corresponds with new knowledge regarding the molecular basis underlying CKD, and they are already showing encouraging preclinical results, with two candidates being evaluated in clinical trials. However, despite recent technological advances, efficient kidney delivery remains challenging, and the presence of off-targets and side-effects precludes development and translation to the clinic. In this review, we provide an overview of the various oligotherapeutic strategies used preclinically, emphasizing the most recent findings in the field, together with the different strategies employed to achieve proper kidney delivery. The use of different nanotechnological platforms, including nanocarriers, nanoparticles, viral vectors or aptamers, and their potential for the development of more specific and effective treatments is also outlined. Full article

(This article belongs to the Special Issue Oligonucleotides-Based Therapeutics)

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