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RNA therapeutics approved for clinical use by May 2022.
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RNA-based therapies are a new, rapidly growing class of drugs that until a few years ago were being used mainly in research in rare diseases. However, the clinical efficacy of recently approved oligonucleotide drugs and the massive success of COVID-19 RNA vaccines has boosted the interest in this type of molecules of both scientists and industry, a...
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... modifications and substitutions affecting the nucleotide bases and the phosphate-sugar backbone have improved their stability and pharmacokinetic properties, while the use of several delivery approaches such as conjugates and nanoparticles has made possible many therapeutic indications [4]. More than a dozen molecules have now received marketing authorization from the Food and Drug Administration (FDA) in the United States of America, European Medicines Agency (EMA) in Europe and/or the Japan Ministry of Health, Labor and Welfare (Table 1), and many others are in ongoing clinical trials [5][6][7]. Several reviews have recently appeared on the topic of RNA therapies, stage of development and options for delivery [4,6,[8][9][10][11][12][13]. ...Context 2
... recent years, many studies have provided the proof of concept of the therapeutic potential of exogenous synthetic siRNAs, chemically modified to enhance stability and prevent nuclease mediated degradation. To date, four siRNA drugs have been approved (Table 1) and clinical trials are ongoing for several disorders [6]. ...Context 3
... approaches have proven successful for liver delivery of therapeutic siRNAs: LNP and conjugation to triantennary Nacetylgalactosamine (GalNAc) ligand that binds to the asialoglycoprotein receptor (ASGPR) in hepatocytes, both for systemic administration. The first LNP-RNAi drug was approved in 2018 to treat polyneuropathy in patients with hereditary amyloidosis transthyretin related (hATTR amyloidosis, OMIM #105210) and three GalNacconjugated RNAi drugs have been approved to date, for treating AHP, PH1 and hypercholesterolemia (familial and non-familial) (Table 1) [9]. This last case represents the first example of an approved RNA drug developed to treat a prevalent disease, which may become the first widely used siRNA drug, after reassuring safety and efficacy data from clinical trials on thousands of patients [9]. ...Context 4
... date, four RNAse H1 recruiting ASO have received approval from one or more regulatory agencies, the first was a PS DNA-based ASO developed for treating CMV retinitis patients (Fomivirsen) ( Table 1). Subsequently approved were allele independent drugs for treatment of familial hypercholesterolemia (Mipomersen targeting ApoB lipoprotein mRNA) (Fig. 2C) and of familial chylomicronemia syndrome, hypertriglyceridemia and familial partial lipodystrophy (Volanesorsen, targeting apolipoprotein CIII mRNA). ...Context 5
... are PS 2'-MOE gapmers, that effectively lower the levels of specific lipids increased in these diseases [31]. In contrast, Inotersen is a gapmer designed to specifically target the mutant TTR mRNA encoding a transthyretin protein with a dominant-negative effect in autosomal dominant hATTR (Table 1) [32]. ...Context 6
... is by far the most successful SSO to date, both clinically (treated patients show significant improvements in motor skills and muscle function) and commercially, achieving more than $4.5 billion in sales by the end of 2019 [1]. In Duchenne muscular dystrophy (DMD), several approved SSOs target ESEs in specific exons, promoting exon skipping to produce a mature transcript with a restored open reading frame coding for a partially functional dystrophin (Table 1) [4]. ...Context 7
... with SSO the splice sites or enhancer elements in the pseudoexon restores normal splicing and this has been proven successful in many preclinical studies in different diseases, including IEM [33,36,37]. Recently, an SSO (Milasen) (Fig. 2D) targeting an activated pseudoexon in the CLN7 gene causing neuronal ceroid lipofuscinosis (NCL, OMIM #610951, a type of Batten's disease) was developed and approved by the FDA for clinical testing just within one year, and, most extraordinary, it was designed for just one patient (Mila) carrying this private mutant allele (Table 1) [38]. This marked the beginning of n = 1 trials for patients with ultra-rare mutations, extreme examples of personalized medicine. ...Context 8
... marked the beginning of n = 1 trials for patients with ultra-rare mutations, extreme examples of personalized medicine. Similarly, the RNA drug Jacifusen was designed and tested in a patient (Jaci Hermstad) suffering from amyotrophic lateral sclerosis with mutations in the FUS gene (Table 1). Unfortunately, both Mila and Jaci died recently. ...Context 9
... are typically identified after iterative enrichment rounds from a random pool of degenerate oligonucleotide sequences and selection on the basis of their binding or functional activities (an in vitro procedure to select functional nucleic acids, termed SELEX) [47]. Only one aptamer-based drug has received approval so far, pegaptanib (Macugen), for the prevention of age-related macular degeneration (Table 1), although many others are now being developed [45]. ...Similar publications
The highly specific induction of RNA interference-mediated gene knockdown, based on the direct application of small interfering RNAs (siRNAs), opens novel avenues towards innovative therapies. Two decades after the discovery of the RNA interference mechanism, the first siRNA drugs received approval for clinical use by the US Food and Drug Administr...
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... They are divided into three generations based on modification. Phosphorothioate backbone modifications are the major representatives of the first-generation ASOs and have sufficient resistance to nuclease degradation; the second generation mainly comprise 2′-O-methyl (2′-OMe) and 2′-O-methoxyethyl (2′-MOE) modifications, while the third-generation ASOs comprise modifications such as locked nucleic acids and phosphorodiamidate modified morpholino oligomers [2,3]. Nusinersen, an 18-mer ASO, belongs to the first and second generations with full phosphorothioate linkage modification and the 2′-MOE groups are substituted for 2′-hydroxy groups of all ribofuranosyl rings [4]. ...
A hydrophilic interaction liquid chromatography tandem mass spectrometry (HILIC/MS/MS) method was developed and validated for the quantitative analysis of the fully phosphorothioate modified oligonucleotide nusinersen. HILIC/MS/MS method is more robust and compatible with mass spectrometry than ion pair reversed-phase liquid chromatography-tandem mass spectrometry (IP-RP-LC/MS/MS). Various types and concentrations of additives and different pH of mobile phase affected the mass spectrometry response, chromatographic peak shape and retention of nusinersen. The optimized extraction method of nusinersen employs hydrophilic-lipophilic balance solid phase extraction, with a recovery of up to 80 %. Chromatographic quantification was performed using a gradient system on an amide column and the mobile phase consisted of ammonium acetate, acetonitrile and water in a certain proportion. The fully phosphorothioate modified nusinersen can obtain a high mass spectrometry response by providing greater peak symmetry and high ionization efficiency in a high-pH mobile phase. Moreover, the significant carry over interference was observed at the pH 6.3 of the mobile phase. Adjusting the pH value up to 10, and the carry over interference disappeared. The lower limit of quantitation of this developed HILIC/MS/MS assay was 30.0 ng/mL and the method was systematic methodology validated. This HILIC/MS/MS method provides an attractive and robust alternative for the quantitative analysis of nusinersen and was applied in the pharmacokinetic study of nusinersen in rabbits.
... These diseases, like COPD and asthma, involve dysregulated immune responses and inflammation (Hegde et al., 2021). Antisense RNAs may influence the expression of key genes involved in inflammation, offering a promising avenue for understanding and potentially targeting the molecular mechanisms underlying these conditions, paving the way for novel therapeutic approaches to manage inflammatory lung diseases (Martinez-Pizarro andDesviat, 2022, Quemener et al., 2022). Pfafenrot et al. utilized circRNAs as antisense molecules targeting the SARS-CoV-2 virus. ...
Circular RNAs (circRNAs) have emerged as pivotal regulators of gene expression and cellular processes in various physiological and pathological conditions. In recent years, there has been a growing interest in investigating the role of circRNAs in inflammatory lung diseases, owing to their potential to modulate inflammation-associated pathways and contribute to disease pathogenesis. Inflammatory lung diseases, like asthma, chronic obstructive pulmonary disease (COPD), and COVID-19, pose significant global health challenges. The dysregulation of inflammatory responses demonstrates a pivotal function in advancing these diseases. CircRNAs have been identified as important players in regulating inflammation by functioning as miRNA sponges, engaging with RNA-binding proteins, and participating in intricate ceRNA networks. These interactions enable circRNAs to regulate the manifestation of key inflammatory genes and signaling pathways. Furthermore, emerging evidence suggests that specific circRNAs are differentially expressed in response to inflammatory stimuli and exhibit distinct patterns in various lung diseases. Their involvement in immune cell activation, cytokine production, and tissue remodeling processes underscores their possible capabilities as therapeutic targets and diagnostic biomarkers. Harnessing the knowledge of circRNA-mediated regulation in inflammatory lung diseases could lead to the development of innovative strategies for disease management and intervention. This review summarizes the current understanding of the role of circRNAs in inflammatory lung diseases, focusing on their regulatory mechanisms and functional implications.
... The introduction of different modifications in the mRNA sequences, such as optimization of the 5'-Cap, 3'-UTR and poly(A) tail, have improved the stability and immunogenicity of the mRNA. In addition, delivery agents like lipid nanoparticles have allowed targeted delivery of mRNA particles to cells/ organs of interest, though new nanoparticle formulations should enhance the potency to reach non-hepatic tissues [139][140][141]. There are different delivery systems for mRNA therapy; the choice depends on the size of the mRNA molecule, the charge, and the tissue that is targeted. ...
... Multiple ASOs have already been approved for clinical use, such as gapmers for familial hypercholesterolemia, hereditary transthyretin amyloidosis and familial chylomicronemia syndrome, and steric-blocking ASOs for Duchenne muscular dystrophy and spinal muscular atrophy. One limitation of this therapy, however, is that ASOs can often only be used for specific pathogenic variants in a certain disorder [140,143]. On the other hand, due to the unique nature of extremely rare private pathogenic variants, ASOs can be considered as versatile therapeutic options for n-of-1 or nof-few studies, if the variant is ASO amenable. An example of a n-of-1 ASO treatment is the development of milasen for one patient with Batten's disease [144]. ...
... miRNA mimics are precursor dsRNA molecules that, as the name implies, mimic the activity of miRNAs and silence the expression of a target gene. On the other hand, miRNA inhibitors (also known as antagomiRs or antimiRs) are ASOs that inhibit a specific miRNA, thereby enhancing the gene expression of the miRNA-targeted gene [140,150]. A phase 2, randomized, double-blind, placebo controlled study of Lademirsen (antimiR-21) in patients with Alport Syndrome was recently terminated due to negative futility analysis (NCT02855268). ...
Newborn screening (NBS) began a revolution in the management of biochemical genetic diseases, greatly increasing the number of patients for whom dietary therapy would be beneficial in preventing complications in phenylketonuria as well as in a few similar disorders. The advent of next generation sequencing and expansion of NBS have markedly increased the number of biochemical genetic diseases as well as the number of patients identified each year. With the avalanche of new and proposed therapies, a second wave of options for the treatment of biochemical genetic disorders has emerged. These therapies range from simple substrate reduction to enzyme replacement, and now ex vivo gene therapy with autologous cell transplantation. In some instances, it may be optimal to introduce nucleic acid therapy during the prenatal period to avoid fetopathy. However, as with any new therapy, complications may occur. It is important for physicians and other caregivers, along with ethicists, to determine what new therapies might be beneficial to the patient, and which therapies have to be avoided for those individuals who have less severe problems and for which standard treatments are available. The purpose of this review is to discuss the "Standard" treatment plans that have been in place for many years and to identify the newest and upcoming therapies, to assist the physician and other healthcare workers in making the right decisions regarding the initiation of both the "Standard" and new therapies. We have utilized several diseases to illustrate the applications of these different modalities and discussed for which disorders they may be suitable. The future is bright, but optimal care of the patient, including and especially the newborn infant, requires a deep knowledge of the disease process and careful consideration of the necessary treatment plan, not just based on the different genetic defects but also with regards to different variants within a gene itself.
... Lastly, we also identified the non-coding RNAs involved in the regulation of autophagy genes in order to increase the interest of researchers in new non-coding RNA targetsRNAbased therapeutics, such as small interfering RNAs, antisense nucleotides, splice-switching antisense oligonucleotides, messenger RNAs, etc., represent a major opportunity and new frontier for drug development. Until May 2022, sixteen RNA therapeutics have received marketing authorization from the Food and Drug Administration (FDA) in the United States of America, European Medicines Agency (EMA) in Europe, and/or the Japan Ministry of Health, Labor and Welfare [106]. Additionally, promising preclinical research has demonstrated the efficiency of small interfering RNA to silence hepatic glycogen synthase 2 (Gys2) expression and effectively prevent glycogen synthesis, glycogen accumulation, hepatomegaly, fibrosis, and nodule development in a mouse model of GSD III [107]. ...
Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype–phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype–phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients.
The last decade (2013–2023) has seen unprecedented successes in the clinical translation of therapeutic antisense oligonucleotides (ASOs). Eight such molecules have been granted marketing approval by the United States Food and Drug Administration (US FDA) during the decade, after the first ASO drug, fomivirsen, was approved much earlier, in 1998. Splice-modulating ASOs have also been developed for the therapy of inborn errors of metabolism (IEMs), due to their ability to redirect aberrant splicing caused by mutations, thus recovering the expression of normal transcripts, and correcting the deficiency of functional proteins. The feasibility of treating IEM patients with splice-switching ASOs has been supported by FDA permission (2018) of the first “N-of-1” study of milasen, an investigational ASO drug for Batten disease. Although for IEM, owing to the rarity of individual disease and/or pathogenic mutation, only a low number of patients may be treated by ASOs that specifically suppress the aberrant splicing pattern of mutant precursor mRNA (pre-mRNA), splice-switching ASOs represent superior individualized molecular therapeutics for IEM. In this work, we first summarize the ASO technology with respect to its mechanisms of action, chemical modifications of nucleotides, and rational design of modified oligonucleotides; following that, we precisely provide a review of the current understanding of developing splice-modulating ASO-based therapeutics for IEM. In the concluding section, we suggest potential ways to improve and/or optimize the development of ASOs targeting IEM.
RNA-based therapeutics have emerged as promising approaches to modulate gene expression and generate therapeutic proteins or antigens capable of inducing immune responses to treat a variety of diseases, such as infectious diseases, cancers, immunologic disorders, and genetic disorders. However, the efficient delivery of RNA molecules into cells poses significant challenges due to their large molecular weight, negative charge, and susceptibility to degradation by RNase enzymes. To overcome these obstacles, viral and non-viral vectors have been developed, including lipid nanoparticles, viral vectors, proteins, dendritic macromolecules, among others. Among these carriers, protein-based delivery systems have garnered considerable attention due to their potential to address specific issues associated with nanoparticle-based systems, such as liver accumulation and immuno-genicity. This review provides an overview of currently marketed RNA drugs, underscores the significance of RNA delivery vector development, delineates the essential characteristics of an ideal RNA delivery vector, and introduces existing protein carriers for RNA delivery. By offering valuable insights, this review aims to serve as a reference for the future development of protein-based delivery vectors for RNA therapeutics.
