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Human Gene Therapy Aug 2015In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various... (Review)
Review
In this review we address the development of oligonucleotide (ON) medicines from a historical perspective by listing the landmark discoveries in this field. The various biological processes that have been targeted and the corresponding ON interventions found in the literature are discussed together with brief updates on some of the more recent developments. Most ON therapies act through antisense mechanisms and are directed against various RNA species, as exemplified by gapmers, steric block ONs, antagomirs, small interfering RNAs (siRNAs), micro-RNA mimics, and splice switching ONs. However, ONs binding to Toll-like receptors and those forming aptamers have completely different modes of action. Similar to other novel medicines, the path to success has been lined with numerous failures, where different therapeutic ONs did not stand the test of time. Since the first ON drug was approved for clinical use in 1998, the therapeutic landscape has changed considerably, but many challenges remain until the expectations for this new form of medicine are met. However, there is room for cautious optimism.
Topics: Animals; Genetic Therapy; History, 20th Century; Humans; MicroRNAs; Oligonucleotides, Antisense; RNA Interference; RNA Stability
PubMed: 26160334
DOI: 10.1089/hum.2015.070 -
Annual Review of Pharmacology and... Jan 2021The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of... (Review)
Review
The genetic basis for most inherited neurodegenerative diseases has been identified, yet there are limited disease-modifying therapies for these patients. A new class of drugs-antisense oligonucleotides (ASOs)-show promise as a therapeutic platform for treating neurological diseases. ASOs are designed to bind to the RNAs either by promoting degradation of the targeted RNA or by elevating expression by RNA splicing. Intrathecal injection into the cerebral spinal fluid results in broad distribution of antisense drugs and long-term effects. Approval of nusinersen in 2016 demonstrated that effective treatments for neurodegenerative diseases can be identified and that treatments not only slow disease progression but also improve some symptoms. Antisense drugs are currently in development for amyotrophic lateral sclerosis, Huntington's disease, Alzheimer's disease, Parkinson's disease, and Angelman syndrome, and several drugs are in late-stage research for additional neurological diseases. This review highlights the advances in antisense technology as potential treatments for neurological diseases.
Topics: Humans; Neurodegenerative Diseases; Oligonucleotides, Antisense; Parkinson Disease; Pharmaceutical Preparations; RNA
PubMed: 33035446
DOI: 10.1146/annurev-pharmtox-010919-023738 -
Hearing Research Dec 2022Hearing loss affects more than 430 million people, worldwide, and is the third most common chronic physical condition in the United States and Europe (GBD Hearing Loss... (Review)
Review
Hearing loss affects more than 430 million people, worldwide, and is the third most common chronic physical condition in the United States and Europe (GBD Hearing Loss Collaborators, 2021; NIOSH, 2021; WHO, 2021). The loss of hearing significantly impacts motor and cognitive development, communication, education, employment, and overall quality of life. The inner ear houses the sensory organs for both hearing and balance and provides an accessible target for therapeutic delivery. Antisense oligonucleotides (ASOs) use various mechanisms to manipulate gene expression and can be tailor-made to treat disorders with defined genetic targets. In this review, we discuss the preclinical advancements within the field of the highly promising ASO-based therapies for hereditary hearing loss disorders. Particular focus is on ASO mechanisms of action, preclinical studies on ASO treatments of hearing loss, timing of therapeutic intervention, and delivery routes to the inner ear.
Topics: Humans; Quality of Life; Hearing Loss; Deafness; Oligonucleotides, Antisense; Gene Expression
PubMed: 35649738
DOI: 10.1016/j.heares.2022.108523 -
Cells Oct 2023Antisense oligonucleotide-based (ASO) therapeutics have emerged as a promising strategy for the treatment of human disorders. Charge-neutral PMOs have promising... (Review)
Review
Antisense oligonucleotide-based (ASO) therapeutics have emerged as a promising strategy for the treatment of human disorders. Charge-neutral PMOs have promising biological and pharmacological properties for antisense applications. Despite their great potential, the efficient delivery of these therapeutic agents to target cells remains a major obstacle to their widespread use. Cellular uptake of naked PMO is poor. Cell-penetrating peptides (CPPs) appear as a possibility to increase the cellular uptake and intracellular delivery of oligonucleotide-based drugs. Among these, the DG9 peptide has been identified as a versatile CPP with remarkable potential for enhancing the delivery of ASO-based therapeutics due to its unique structural features. Notably, in the context of phosphorodiamidate morpholino oligomers (PMOs), DG9 has shown promise in enhancing delivery while maintaining a favorable toxicity profile. A few studies have highlighted the potential of DG9-conjugated PMOs in DMD (Duchenne Muscular Dystrophy) and SMA (Spinal Muscular Atrophy), displaying significant exon skipping/inclusion and functional improvements in animal models. The article provides an overview of a detailed understanding of the challenges that ASOs face prior to reaching their targets and continued advances in methods to improve their delivery to target sites and cellular uptake, focusing on DG9, which aims to harness ASOs' full potential in precision medicine.
Topics: Animals; Humans; Oligonucleotides, Antisense; Cell-Penetrating Peptides; Oligonucleotides; Morpholinos; Muscular Dystrophy, Duchenne; Muscular Atrophy, Spinal
PubMed: 37830609
DOI: 10.3390/cells12192395 -
Drug Discoveries & Therapeutics 2016Therapeutic oligonucleotides are promising technologies. Nevertheless, improvement of their efficacy is an important issue. Introducing this drug delivery system (DDS)... (Review)
Review
Therapeutic oligonucleotides are promising technologies. Nevertheless, improvement of their efficacy is an important issue. Introducing this drug delivery system (DDS) makes for a great enhancement for delivery of oligonucleotides to targeted tissue or cells. The strategy of DDS for therapeutic oligonucleotides is divided into four categories, A) single piece of oligonucleotide, B) oligonucleotide-ligand conjugate, C) oligonucleotide-polymer conjugate, and D) nanoparticle. In this review we will describe those basic concepts, especially for the technology of conjugating ligand. In addition, we developed a new technology, heteroduplex oligonucleotide (HDO), binding ligand-molecule to antisense oligonucleotide indirectly. We also outline α-tocopherol (a natural isomer of vitamin E) conjugated HDO.
Topics: Drug Delivery Systems; Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA, Small Interfering; Tocopherols
PubMed: 27890899
DOI: 10.5582/ddt.2016.01065 -
Journal of Cystic Fibrosis : Official... Jan 2020Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation.
METHODS
This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV > 70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1 s (ppFEV), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS).
RESULTS
Single and multiple doses of inhaled eluforsen up to 50 mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment.
CONCLUSIONS
Inhaled eluforsen up to 50 mg dosed 3 times per week for 4 weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.
Topics: Administration, Inhalation; Adult; Cross-Over Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Dose-Response Relationship, Drug; Double-Blind Method; Drug Monitoring; Female; Humans; Male; Mutation; Oligonucleotides; Oligonucleotides, Antisense; Respiratory Function Tests; Symptom Assessment; Treatment Outcome
PubMed: 31182369
DOI: 10.1016/j.jcf.2019.05.014 -
International Journal of Molecular... May 2021Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense... (Review)
Review
Spinal muscular atrophy (SMA) is an autosomal recessive genetic disorder leading to paralysis, muscle atrophy, and death. Significant advances in antisense oligonucleotide treatment and gene therapy have made it possible for SMA patients to benefit from improvements in many aspects of the once devastating natural history of the disease. How the depletion of survival motor neuron (SMN) protein, the product of the gene implicated in the disease, leads to the consequent pathogenic changes remains unresolved. Over the past few years, evidence toward a potential contribution of gastrointestinal, metabolic, and endocrine defects to disease phenotype has surfaced. These findings ranged from disrupted body composition, gastrointestinal tract, fatty acid, glucose, amino acid, and hormonal regulation. Together, these changes could have a meaningful clinical impact on disease traits. However, it is currently unclear whether these findings are secondary to widespread denervation or unique to the SMA phenotype. This review provides an in-depth account of metabolism-related research available to date, with a discussion of unique features compared to other motor neuron and related disorders.
Topics: Animals; Disease Models, Animal; Genetic Therapy; Humans; Motor Neurons; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Phenotype; Survival of Motor Neuron 1 Protein
PubMed: 34072857
DOI: 10.3390/ijms22115913 -
Nucleic Acids Research Feb 2018RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and... (Review)
Review
RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and oligonucleotide mimics offer a general strategy for controlling processes that affect disease. The two primary antisense approaches for regulating expression through recognition of cellular RNAs are single-stranded antisense oligonucleotides and duplex RNAs. This review will discuss the chemical modifications and molecular mechanisms that make synthetic nucleic acid drugs possible. Lessons learned from recent clinical trials will be summarized. Ongoing clinical trials are likely to decisively test the adequacy of our current generation of antisense nucleic acid technologies and highlight areas where more basic research is needed.
Topics: Alternative Splicing; Clinical Trials as Topic; Humans; MicroRNAs; Oligonucleotides, Antisense; Protein Biosynthesis; Proteins; RNA Interference; RNA, Double-Stranded
PubMed: 29240946
DOI: 10.1093/nar/gkx1239 -
Bioorganic & Medicinal Chemistry Jan 2023This study was aimed at developing a novel platform for tetravalent conjugation of 4-arm polyethylene glycol (PEG) with an antisense oligonucleotide (ASO). The ASO...
This study was aimed at developing a novel platform for tetravalent conjugation of 4-arm polyethylene glycol (PEG) with an antisense oligonucleotide (ASO). The ASO technology has several limitations, such as low cellular uptake, poor nuclease stability, and short half-life. PEG-conjugated ASOs may result in an improvement in the pharmacokinetic behavior of the drug. Moreover, PEGylation can reduce enzymatic degradation and renal excretion of the conjugates, thereby, increasing its blood stability and retention time. In this study, we successfully synthesized PEG-ASO conjugate consisting of 4-arm-PEG and four molecules of ASO (4-arm-PEG-tetra ASO). Its hybridization ability with complementary RNA, enzymatic stability, and in vitro gene silencing ability were evaluated. No significant difference in hybridization ability was observed between 4-arm-PEG-tetra ASO and the parent ASO. In addition, gene silencing activity of the 4-arm-PEG-tetra ASO was observed in vitro. However, the in vitro activity of the 4-arm-PEG-tetra ASO was slightly reduced as that of the parent ASO. Moreover, the 4-arm-PEG-tetra ASO showed appreciable stability in cellular extract, suggesting that it hybridizes with mRNA in its intact form, without being cleaved in the cell, and exhibits ASO activity.
Topics: Oligonucleotides, Antisense; Polyethylene Glycols; Oligonucleotides; RNA, Messenger
PubMed: 36587552
DOI: 10.1016/j.bmc.2022.117149 -
European Journal of Cell Biology Jun 2023Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the... (Review)
Review
Spinal muscular atrophy (SMA), the most common genetic cause of infantile death, is caused by a mutation in the survival of motor neuron 1 gene (SMN1), leading to the death of motor neurons and progressive muscle weakness. SMN1 normally produces an essential protein called SMN. Although humans possess a paralogous gene called SMN2, ∼90% of the SMN it produces is non-functional. This is due to a mutation in SMN2 that causes the skipping of a required exon during splicing of the pre-mRNA. The first treatment for SMA, nusinersen (brand name Spinraza), was approved by the FDA in 2016 and by the EMU in 2017. Nusinersen is an antisense oligonucleotide-based therapy that alters the splicing of SMN2 to make functional full-length SMN protein. Despite the recent advancements in antisense oligonucleotide therapy and SMA treatment development, nusinersen is faced with a multitude of challenges, such as intracellular and systemic delivery. In recent years, the use of peptide-conjugated phosphorodiamidate morpholino oligomers (PPMOs) in antisense therapy has gained interest. These are antisense oligonucleotides conjugated to cell-penetrating peptides such as Pips and DG9, and they have the potential to address the challenges associated with delivery. This review focuses on the historic milestones, development, current challenges, and future perspectives of antisense therapy for SMA.
Topics: Humans; Oligonucleotides, Antisense; Muscular Atrophy, Spinal; Morpholinos; Motor Neurons; RNA Splicing
PubMed: 37295266
DOI: 10.1016/j.ejcb.2023.151326