DOCSLIB.ORG

The Rna Platform a Revolution in Therapeutics

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Rna Platform a Revolution in Therapeutics THE RNA PLATFORM A REVOLUTION IN THERAPEUTICS Pharmaceutical Paul-Philippe Champagne, PhD, PEng Senior Process Engineer Divyang Patel CQV and Compliance Specialist The RNA platform is a revolution in therapeutics The recent coronavirus pandemic has revolutionized medical innovation. + The rapid growth in requirement for therapeutics, including vaccines, 30 has brought the RNA platform to the forefront. However, the relevant literature is focused either exclusively on the molecular biology of RNA or on the development of RNA products. As such, we provide you with YEARS an accessible introduction on this revolutionary technology that bridges OF EXPERIENCE IN THE the gap between the science and its application. We begin by giving you PHARMA an overview of RNA and how biopharmaceutical companies are using BIOTECH & this novel technology in a wealth of diverse pharmaceutical products. medical device We also discuss key processes for the development and manufacture of RNA therapies, with mRNA vaccines as a case study. Lastly, we MARKET highlight the potential of this technology and discuss facility delivery. Messenger ribonucleic acid (mRNA) is a naturally occurring A plethora of RNA products molecule in the cell. It is primarily used as an intermediate in the transfer of genetic information encoded in deoxyribonucleic acid Owing to the versatile nature of the RNA platform, it is being used (DNA) to produce proteins. DNA is frst transcribed into mRNA in to develop vaccines for infuenza, coronavirus, and other infectious the nucleus of the eukaryotic cell, and then the mRNA is translated diseases (Jackson et al., 2020; Pardi et al., 2018). mRNA vaccines into proteins in the cell’s cytoplasm. are also in progress for human cancers (Pardi et al., 2018). There are numerous other therapeutics in the pipeline that use some mRNA technology allows for the safe delivery of an intact sequence facet of the RNA platform, and it is likely more therapies will be of interest to the host cell (Hoecke & Roose, 2019; Jackson et al., approved. For example, mRNA is currently being explored to 2020; Pardi et al., 2018). The sequence can code for an antigen, a express mAbs (Hoecke & Roose, 2019). These molecules would monoclonal antibody (mAb), or any other therapeutic target. The then trigger the immune response in the presence of their platform is revolutionary because modifed mRNA is more stable respective antigens. Likewise, the mRNA platform is being used for than native mRNA and is not immunogenic, thus reducing the the development of single-stranded antisense oligonucleotides immune response and improving the translation effciency. In (ASOs) (Deweerdt, 2019). ASOs bind to their complementary target addition, the formulation and encapsulation of the mRNA is critical mRNA sequence and can obstruct the splicing process, hinder 5’ to the technology since it allows the molecule to be delivered intact cap formation, mark the mRNA for destruction, and block to target cells. The mRNA is typically encapsulated in a lipid translation by the ribosome with steric obstruction. Similarly, nanoparticle, which further limits the immune response that would mRNA technology can be utilized to block translation of the mRNA trigger its destruction by the immune system. Crucially, the mRNA of interest through RNA interference (RNAi) (Deweerdt, 2019). sequence does not penetrate the cell nucleus and does not insert RNAi can occur through microRNAs and small interfering RNAs itself into the genome. Therefore, there is no genetic modifcation. (siRNAs), which can tag the mRNA for degradation and inhibit These features have allowed the rapid development of current protein translation in a manner akin to ASOs. In addition, mRNA can mRNA vaccines for the SARS-Cov-2 coronavirus pandemic. Indeed, also be employed to modulate the function of a target protein via responding to the threat of emerging coronavirus variants, mRNA the expression of RNA aptamers (Deweerdt, 2019). Table 1 vaccine manufacturers have been able to adjust their existing illustrates a sample of RNA therapies. mRNA sequences to develop new vaccine candidates. PHARMACEUTICAL / / THE RNA PLATFORM / / 2 Therapy Disease Generic/ Target Organization(s) Status Approval Type Type Brand Breast cancer BioNTech Ongoing N/A N/A Cancer Melanoma Radboud University Ongoing N/A N/A Prostate cancer Oslo University Hospital Ongoing N/A N/A HIV Erasmus Medical Centre Ongoing N/A N/A Infuenza Moderna Ongoing N/A N/A Vaccine mRNA-1273/ EMA/FDA/ COVID-19 Infectious Moderna Completed HPFB/MHRA Vaccine SARS-Cov-2 Moderna EMA/FDA/ Tozinameran/ Pfzer-BioNTech Completed HPFB/MHRA Comirnaty Akcea Therapeutics-Ionis EMA/FDA/ Inotersen/ Autoimmune Amyloidosis Completed Pharmaceuticals MHRA Tegsedi Duchenne muscular Eteplirsen/ ASO Sarepta Therapeutics Completed FDA dystrophy Exondys 51 Genetic Ionis EMA/FDA/ Nusinersen/ Spinal muscular atrophy Completed Pharmaceuticals-Biogen HPFB/MHRA Spinraza BioNTech-Johannes Cancer Lymphoblastic leukemia Ongoing N/A N/A Gutenberg University Georgia Institute of mAb Infectious RSV Technology-Emory Ongoing N/A N/A University CureVac-Acuitas Toxin Botulism Therapeutics-Tufts Ongoing N/A N/A University RNA Neuro- Pegaptanib/ AMD Astellas Pharma Completed EMA/FDA/HPFB aptamer degenerative Macugen Alnylam Patisiran/ siRNA Autoimmune Amyloidosis Completed EMA/FDA Pharmaceuticals Onpattro Table 1: Overview of the array of RNA therapeutics. Table Legend: AMD, age-related macular degeneration; ASO, antisense oligonucleotides; EMA, European Medicines Agency; FDA, Food and Drug Administration of the United States; HIV, human immunodefciency virus; HPFB, Health Products and Food Branch of Health Canada; mAB, monoclonal antibody; MHRA, Medicines and Healthcare products Regulatory Agency of the United Kingdom; mRNA, messenger ribonucleic acid; RSV, respiratory syncytial virus; SARS-Cov-2, severe acute respiratory syndrome coronavirus 2 (COVID-19); siRNA, small interfering ribonucleic acid. Source: Deweerdt, 2019; Hoecke & Roose, 2019; Jackson et al., 2020; Pardi et al., 2018. PHARMACEUTICAL / / THE RNA PLATFORM / / 3 A PRIMER ON THE mRNA MANUFACTURING PROCESS Generation of the DNA template (or transcription template) The mRNA transcript manufacturing process begins with the synthesis of the template plasmid DNA (pDNA). Molecular biologists design the DNA template which includes the genetic sequence of interest that encodes for either a candidate antigen or any therapeutic protein. Once designed and produced in small quantities, the pDNA is thereafter introduced into a bacterial host (usually Escherichia coli) for its amplifcation through cell expansion and plasmid replication. pDNA amplifcation begins in the recombinant bacterial shake fask culture and is then scaled up to a microbial fermenter. At the end of the cultivation period, the pDNA is extracted from the bacterial culture and is purifed. Typically, the harvested cells are lysed using a cell homogenizer and the pDNA is subsequently recovered from the clarifed lysate. A continuous centrifuge or a microfltration system is normally used for the clarifcation step. The pDNA is further purifed by chromatography to remove host cells and endotoxins, and flter sterilized. A diafltration step may be added to exchange the buffer for in vitro mRNA transcription. The production of pDNA can be outsourced or implemented in-house by any biopharmaceutical organization depending on the DNA requirements and scale of production. In vitro transcription of mRNA Once generated, the purifed pDNA is enzymatically linearized and added to a mixture of enzymes and nucleotides (the RNA building blocks) for the synthesis of mRNA by the enzyme RNA polymerase. This enzyme transcribes the target genetic sequence of the linearized pDNA into mRNA. After mRNA generation is complete, the template DNA is enzymatically digested with a deoxyribonuclease (DNase), and the bulk mRNA is purifed via a series of chromatography steps. The mRNA transcripts are subsequently capped on their 5’ end and then further purifed. Active research and development efforts are underway to combine the mRNA transcription and 5’-capping into one step. The capped mRNA is further purifed by chromatography, diafltered for buffer exchange, and sterile fltered for the subsequent formulation. The purity of the mRNA transcript is the key to minimizing risks of side effects and/or lack of effcacy after vaccine administration. Formulation of the mRNA transcript (drug substance) Various technologies for the formulation of mRNA vaccines exist, with microfuidic encapsulation with liposomes the customary choice. We recommend this technology, compared to others such as sonication and extrusion, since it has the advantage of consistently achieving greater control over the liposome size and favoring higher encapsulation effciencies of the drug substance. The mRNA transcript in an aqueous buffer and the lipids dissolved typically in ethanol are homogenized by microjet impingement mixing. During the mixing process, the lipids and mRNA molecules spontaneously self- assemble into loaded liposomes. The lipid types are carefully selected and buffer conditions optimized for the effcient encapsulation of the mRNA and for the correct liposome self-assembly (Buschmann et al., 2021; Kis et al., 2020). We believe, and experts agree, that this step may be one of the major bottlenecks of the manufacturing process as technologies allowing the scale up of this formulation are scarce relative to the current unprecedented demand (Lowe, 2021). The
Load more

Recommended publications
  • Mrna Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection
    International Journal of Molecular Sciences Review mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection 1, 1, 2 1,3, Shuqin Xu y, Kunpeng Yang y, Rose Li and Lu Zhang * 1 State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; [email protected] (S.X.); [email protected] (K.Y.) 2 M.B.B.S., School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; [email protected] 3 Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China * Correspondence: [email protected]; Tel.: +86-13524278762 These authors contributed equally to this work. y Received: 30 July 2020; Accepted: 30 August 2020; Published: 9 September 2020 Abstract: Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis.
    [Show full text]
  • Download Article (PDF)
    DNA and RNA Nanotechnology 2015; 2: 42–52 Mini review Open Access Martin Panigaj*, Jakob Reiser Aptamer guided delivery of nucleic acid-based nanoparticles DOI 10.1515/rnan-2015-0005 Evolution of Ligands by Exponential enrichment) [4,5]. Received July 15, 2015; accepted October 3, 2015 Nucleic acid-based aptamers are especially well suited Abstract: Targeted delivery of bioactive compounds is a for the delivery of nucleic acid-based therapeutics. Any key part of successful therapies. In this context, nucleic nucleic acid with therapeutic potential can be linked acid and protein-based aptamers have been shown to to an aptamer sequence [6], resulting in a bivalent bind therapeutically relevant targets including receptors. molecule endowed with a targeting aptamer moiety and In the last decade, nucleic acid-based therapeutics a functional RNA/DNA moiety like a small interfering coupled to aptamers have emerged as a viable strategy for RNA (siRNA), a micro RNA (miRNA), a miRNA antagonist cell specific delivery. Additionally, recent developments (antimiR), deoxyribozymes (DNAzymes), etc. In addition in nucleic acid nanotechnology offer an abundance of to the specific binding, many aptamers upon receptor possibilities to rationally design aptamer targeted RNA recognition elicit antagonistic or agonistic responses that, or DNA nanoparticles involving combinatorial use of in combination with conjugated functional nucleic acids various intrinsic functionalities. Although a host of issues have the potential of synergism. Since the first report including stability, safety and intracellular trafficking describing an aptamer-siRNA delivery approach in 2006 remain to be addressed, aptamers as simple functional many functional RNAs and DNAs conjugated to aptamer chimeras or as parts of multifunctional self-assembled sequences have been tested in vitro and in vivo [7-9].
    [Show full text]
  • Recent Advances in Mrna Vaccine Delivery
    Nano Research 2018, 11(10): 5338–5354 https://doi.org/10.1007/s12274-018-2091-z Recent advances in mRNA vaccine delivery Lu Tan and Xun Sun () Key Laboratory of Drug Targeting and Novel Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China Received: 14 March 2018 ABSTRACT Revised: 30 April 2018 In recent years, messenger RNA (mRNA) vaccines have been intensively studied Accepted: 4 May 2018 in the fields of cancer immunotherapy and infectious diseases because of their excellent efficacy and safety profile. Despite significant progress in the rational © Tsinghua University Press design of mRNA vaccines and elucidation of their mechanism of action, their and Springer-Verlag GmbH widespread application is limited by the development of safe and effective Germany, part of Springer delivery systems that protect them from ubiquitous ribonucleases (RNases), Nature 2018 facilitate their entry into cells and subsequent escape from endosomes, and target them to lymphoid organs or particular cells. Some mRNA vaccines based KEYWORDS on lipid carriers have entered clinical trials. Vaccines based on polymers, while messenger RNA (mRNA) not as clinically advanced as lipid vectors, show considerable potentials. In this vaccines, review, we discuss the necessity of formulating mRNA vaccines with delivery delivery systems, systems, and we provide an overview of reported delivery systems. polymer, lipid 1 Introduction and their complex composition can trigger adverse effects [3]. In contrast, mRNA vaccines express well- Messenger RNA (mRNA) vaccines carry transcripts defined antigens that induce focused immune responses encoding antigens, and use the host cell translational specifically against the encoded antigens [4].
    [Show full text]
  • RNA-Based Therapeutics: Current Progress and Future Prospects
    CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector Chemistry & Biology Review RNA-Based Therapeutics: Current Progress and Future Prospects John C. Burnett1 and John J. Rossi1,* 1Department of Molecular and Cellular Biology, Beckman Research Institute of the City of Hope, Duarte, CA 91010, USA *Correspondence: [email protected] DOI 10.1016/j.chembiol.2011.12.008 Recent advances of biological drugs have broadened the scope of therapeutic targets for a variety of human diseases. This holds true for dozens of RNA-based therapeutics currently under clinical investigation for diseases ranging from genetic disorders to HIV infection to various cancers. These emerging drugs, which include therapeutic ribozymes, aptamers, and small interfering RNAs (siRNAs), demonstrate the unprece- dented versatility of RNA. However, RNA is inherently unstable, potentially immunogenic, and typically requires a delivery vehicle for efficient transport to the targeted cells. These issues have hindered the clinical progress of some RNA-based drugs and have contributed to mixed results in clinical testing. Nevertheless, promising results from recent clinical trials suggest that these barriers may be overcome with improved synthetic delivery carriers and chemical modifications of the RNA therapeutics. This review focuses on the clinical results of siRNA, RNA aptamer, and ribozyme therapeutics and the prospects for future successes. Introduction synthesizing modified RNA and DNA molecules have increased Since the milestone
    [Show full text]
  • Covid 3 Edward Hammond.Pmd
    TWN Series on Intellectual Property and COVID-19 TWNT h i r d W o r l d N e t w o r k Vaccines www.twn.my 3 August 2020 Patent dispute looms as a major complication for Moderna’s COVID-19 vaccine Edward Hammond Moderna’s candidate COVID-19 vaccine, mRNA-1273, on which the US government has placed one of its largest pandemic bets, appears to be ensnared in a serious patent dispute that could impact the vaccine’s production and price. The problem lies in a fight between Moderna and a Canadian biotech company named Arbutus, formerly Tekmira, which holds a patent on mRNA vaccine formulations that Moderna’s vaccine may infringe on. Moderna denies that it needs a licence to Arbutus’ patent in order to produce mRNA-1273.1 But a recent pre- publication paper with Moderna co-authors2 states that mRNA-1273’s formulation is one that appears to squarely fall within the claims of a 2011 Arbutus patent3 that covers particular ratios of ingredients in an mRNA vaccine. Although the pre-publication paper was released only weeks ago in mid-June, Moderna claims that the mRNA-1273 composition that it describes is a “research formulation” that will be replaced with an alternative when the vaccine goes into production. Asked to describe the new formulation, Moderna declined, telling Forbes magazine that “we are not disclosing our proprietary ratios at this time.”4 Before the pandemic, Moderna was working with United States government support on a vaccine against MERS (Middle East Respiratory Syndrome), a coronavirus “cousin” of SARS-CoV-2 that causes COVID- 19.
    [Show full text]
  • Small Interfering RNA from the Lab Discovery to Patients' Recovery
    Small interfering RNA from the lab discovery to patients’ recovery Marie Caillaud, Mévidette El Madani, Liliane Massaad-Massade To cite this version: Marie Caillaud, Mévidette El Madani, Liliane Massaad-Massade. Small interfering RNA from the lab discovery to patients’ recovery. Journal of Controlled Release, Elsevier, 2020, 321, pp.616-628. 10.1016/j.jconrel.2020.02.032. hal-02988620 HAL Id: hal-02988620 https://hal.archives-ouvertes.fr/hal-02988620 Submitted on 19 Nov 2020 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. 1 Small interfering RNA from the lab discovery to patients’ recovery 2 3 Marie Caillaud1, Mévidette El Madani1 and, Liliane Massaad-Massade1* 4 5 1 Université Paris-Saclay, Inserm 1195, Bâtiment Gregory Pincus, 80 rue du Général Leclerc, 6 94276 Le Kremlin-Bicêtre, France 7 8 9 1 *: Correspondance to Liliane MASSADE, PhD, Université Paris-Saclay, Inserm 1195, 10 Bâtiment Gregory Pincus, 80 rue du Général Leclerc, 94276 Le Kremlin-Bicêtre, France 11 12 13 Key words : siRNA, delivery, nanotechnology, formulation, galenic, clinical studies 14 1 1 Abstract 2 In 1998, the RNA interference discovery by Fire and Mello revolutionized the scientific and 3 therapeutic world.
    [Show full text]
  • Correction for Bell Et Al., in Silico Design and Validation of High-Affinity RNA Aptamers Targeting Epithelial Cellular Adhesion
    Correction BIOPHYSICS AND COMPUTATIONAL BIOLOGY, CHEMISTRY Correction for “In silico design and validation of high-affinity RNA aptamers targeting epithelial cellular adhesion molecule dimers,” by David R. Bell, Jeffrey K. Weber, Wang Yin, Tien Huynh, Wei Duan, and Ruhong Zhou, which was first published March 31, 2020; 10.1073/pnas.1913242117 (Proc. Natl. Acad. Sci. U.S.A. 117, 8486–8493). The authors note that an additional affiliation was incorrectly identified for David R. Bell. This author’s sole affiliation should be listed as Computational Biological Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598. The online version has been corrected. Published under the PNAS license. Published February 8, 2021. www.pnas.org/cgi/doi/10.1073/pnas.2100827118 CORRECTION PNAS 2021 Vol. 118 No. 7 e2100827118 https://doi.org/10.1073/pnas.2100827118 | 1of1 Downloaded by guest on September 24, 2021 In silico design and validation of high-affinity RNA aptamers targeting epithelial cellular adhesion molecule dimers David R. Bella,1, Jeffrey K. Webera,1, Wang Yinb,1, Tien Huynha, Wei Duanb,2, and Ruhong Zhoua,c,d,2 aComputational Biological Center, IBM Thomas J. Watson Research Center, Yorktown Heights, NY 10598; bSchool of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia; cDepartment of Chemistry, Columbia University, New York, NY 10027; and dInstitute of Quantitative Biology, Zhejiang University, 310027 Hangzhou, China Edited by Peter Schuster, University of Vienna, Vienna, Austria, and approved March 6, 2020 (received for review August 1, 2019) Nucleic acid aptamers hold great promise for therapeutic applica- modes to the target biomolecule. Although several groups have tions due to their favorable intrinsic properties, as well as high- sought to improve protein–RNA docking (16, 17), whole-molecule throughput experimental selection techniques.
    [Show full text]
  • Mrna Vaccines for Infectious Diseases: Principles, Delivery and Clinical Translation
    REVIEWS mRNA vaccines for infectious diseases: principles, delivery and clinical translation Namit Chaudhary 1, Drew Weissman2 and Kathryn A. Whitehead 1,3 ✉ Abstract | Over the past several decades, messenger RNA (mRNA) vaccines have progressed from a scepticism- inducing idea to clinical reality. In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts. Although it is now clear that mRNA vaccines can rapidly and safely protect patients from infectious disease, additional research is required to optimize mRNA design, intracellular delivery and applications beyond SARS-CoV-2 prophylaxis. In this Review, we describe the technologies that underlie mRNA vaccines, with an emphasis on lipid nanoparticles and other non-viral delivery vehicles. We also overview the pipeline of mRNA vaccines against various infectious disease pathogens and discuss key questions for the future application of this breakthrough vaccine platform. Vaccination is the most effective public health inter- and excessive immunostimulation. Fortunately, a few vention for preventing the spread of infectious dis- tenacious researchers and companies persisted. And eases. Successful vaccination campaigns eradicated over the past decade, by determining mRNA pharma- life- threatening diseases such as smallpox and nearly cology, developing effective delivery vehicles and con- eradicated polio1, and the World Health Organization trolling mRNA immunogenicity, interest in clinical estimates that vaccines
    [Show full text]
  • 2021.07.01.21259831V1.Full.Pdf
    medRxiv preprint doi: https://doi.org/10.1101/2021.07.01.21259831; this version posted July 2, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. 1 A phase 1/2 randomized, double-blinded, placebo controlled ascending dose trial to assess 2 the safety, tolerability and immunogenicity of ARCT-021 in healthy adults 3 4 Jenny G. Low, M.R.C.P., M.P.H., Ruklanthi de Alwis, M.P.H., Ph.D., Shiwei Chen, Ph.D., 5 Shirin Kalimuddin, M.R.C.P., M.P.H., Yan Shan Leong, B.Sc., Tania Ken Lin Mah, B.Sc,, 6 Natalene Yuen B.Sc., Hwee Cheng Tan, Summer L Zhang M.Sc., Jean X.Y. Sim, M.R.C.P, 7 Yvonne F.Z. Chan, M.R.C.P., Ayesa Syenina, PhD., Jia Xin Yee, B.Sc., Eugenia Z. Ong, Ph.D., 8 Rose Sekulovich, Ph.D., Brian B. Sullivan, Ph.D., Kelly Lindert, M.D., Sean B. Sullivan, Ph.D., 9 Pad Chivukula, Ph.D., Steven G. Hughes M.B.,B.S., M.B.A., F.R.C.P., Eng Eong. Ooi, B.M., 10 B.S., Ph.D. 11 12 Correspondence to: 13 Steven G Hughes 14 Arcturus Therapeutics, Inc., 10628 Science Center Drive, Suite 250, San Diego, CA92121, USA. 15 Email: [email protected] NOTE: This preprint reports new research that has not been certified1 by peer review and should not be used to guide clinical practice.
    [Show full text]
  • Are Viral Vectors Any Good for Rnai Antiviral Therapy? "2279
    viruses Editorial Are Viral Vectors Any Good for RNAi y Antiviral Therapy? Kenneth Lundstrom PanTherapeutics, Route de Lavaux 49, CH1095 Lutry, Switzerland; [email protected] Editorial to Special Issue RNA Interference (RNAi) for Antiviral Therapy. y Received: 15 October 2020; Accepted: 19 October 2020; Published: 20 October 2020 Abstract: RNA interference (RNAi) represents a novel approach for alternative antiviral therapy. However, issues related to RNA delivery and stability have presented serious obstacles for obtaining good therapeutic efficacy. Viral vectors are capable of efficient delivery of RNAi as short interfering RNA (siRNA), short hairpin RNA (shRNA) and micro-RNA (miRNA). Efficacy in gene silencing for therapeutic applications against viral diseases has been demonstrated in various animal models. Rotavirus (RV) miR-7 can inhibit rotavirus replication by targeting the RV nonstructural protein 5. Viral gene silencing by targeting the RNAi pathway showed efficient suppression of hepatitis B virus replication by adeno-associated virus (AAV)-based delivery of RNAi hepatitis B virus (HBV) cassettes. Hepatitis C virus replication has been targeted by short hairpin RNA molecules expressed from lentivirus vectors. Potentially, RNAi-based approaches could be suitable for antiviral drugs against COVID-19. Keywords: gene silencing; RNAi; shRNA; miRNA; viral vector; viral replication; antiviral drugs; COVID-19 1. Introduction Although the first antiviral drug against herpes simplex virus, idoxuridine, has been on the market since 1963, not too many efficient antiviral drugs have been developed during the past 60 years. There is, however, an urgent need for novel antiviral drugs, particularly due to the current devastating COVID-19 pandemic [1]. Gene silencing, particularly the application of RNA interference (RNAi), has presented a novel alternative approach for drug development.
    [Show full text]
  • RNA Therapeutics on the Rise
    NEWS & ANALYSIS FROM THE ANALYST’s COUCH RNA therapeutics on the rise Feng Wang, Travis Zuroske and Jonathan K. Watts Digifoto Bronze/ Alamy Stock Photo The broad spectrum of options for increased 94.2% from 2015 to 2020. from Informa Pharma Intelligence’s therapeutic targeting of RNA has attracted Three representative mRNA therapeutic Biomedtracker. Of these drug candidates, substantial interest from both academic companies (Moderna Therapeutics, 63% are in the pre-IND stage, 32% are in research institutes and pharmaceutical BioNtech, and CureVac) attracted early- stage clinical trials (phase I or II), companies. With a growing number of US$2.8 billion of private investment since 3% are in phase III and 5 drugs are awaiting approved RNA therapeutics now generating 2015. Notably, Moderna set a record for regulatory decisions. significant profits, the level of investment the biggest biotech IPO with its value at The largest focus for all three modalities in the field has grown. In this article, we roughly $7.6 billion in 2018. Since 2017, is oncology, encompassing 22% of oligo- analyse investment data for companies RNA- related small molecule companies nucleotide candidates and 45% of mRNA developing RNA therapeutics and their have raised significant investment, including candidates. Beyond oncology, oligonucleo- pipelines. those targeting RNA directly ($262 million tide biodistribution has shaped pipeline to Arrakis, Expansion, Skyhawk and priorities. N-acetylgalactosamine (GalNAc) Investment focus for RNA therapeutics Ribometrix) and those targeting conjugation and lipid nano particle To understand where this investment is epitranscriptomics- related proteins approaches enable robust delivery of focused, we categorized RNA therapeutics ($194 million to Accent, Storm, Gotham oligonucleotides into hepatocytes, which into three groups (oligonucleotides, mRNA, and Twentyeight- Seven Therapeutics).
    [Show full text]
  • Opportunities and Challenges in the Delivery of Mrna-Based Vaccines
    pharmaceutics Review Opportunities and Challenges in the Delivery of mRNA-Based Vaccines Abishek Wadhwa , Anas Aljabbari , Abhijeet Lokras , Camilla Foged and Aneesh Thakur * Department of Pharmacy, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen Ø, Denmark; [email protected] (A.W.); [email protected] (A.A.); [email protected] (A.L.); [email protected] (C.F.) * Correspondence: [email protected]; Tel.: + 45-3533-3938; Fax: +45-3533-6001 Received: 28 December 2019; Accepted: 26 January 2020; Published: 28 January 2020 Abstract: In the past few years, there has been increasing focus on the use of messenger RNA (mRNA) as a new therapeutic modality. Current clinical efforts encompassing mRNA-based drugs are directed toward infectious disease vaccines, cancer immunotherapies, therapeutic protein replacement therapies, and treatment of genetic diseases. However, challenges that impede the successful translation of these molecules into drugs are that (i) mRNA is a very large molecule, (ii) it is intrinsically unstable and prone to degradation by nucleases, and (iii) it activates the immune system. Although some of these challenges have been partially solved by means of chemical modification of the mRNA, intracellular delivery of mRNA still represents a major hurdle. The clinical translation of mRNA-based therapeutics requires delivery technologies that can ensure stabilization of mRNA under physiological conditions. Here, we (i) review opportunities and challenges in the delivery of mRNA-based therapeutics with a focus on non-viral delivery systems, (ii) present the clinical status of mRNA vaccines, and (iii) highlight perspectives on the future of this promising new type of medicine.
    [Show full text]