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Nucleic Acid Therapeutics Apr 2023Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional... (Review)
Review
Drug Metabolism and Pharmacokinetics of Antisense Oligonucleotide Therapeutics: Typical Profiles, Evaluation Approaches, and Points to Consider Compared with Small Molecule Drugs.
Oligonucleotide therapeutics are attracting attention as a new treatment modality for a range of diseases that have been difficult to target using conventional approaches. Technical advances in chemical modification and drug delivery systems have led to the generation of compounds with excellent profiles as pharmaceuticals, and 16 oligonucleotide therapeutics have been marketed to date. There is a growing need to develop optimal and efficient approaches to evaluate drug metabolism and pharmacokinetics (DMPK) and drug-drug interactions (DDIs) of oligonucleotide therapeutics. The DMPK/DDI profiles of small molecule drugs are highly diverse depending on their structural and physicochemical characteristics, whereas oligonucleotide therapeutics share similar DMPK profiles within each chemistry type. Most importantly, the mechanisms and molecules involved in the distribution and metabolism of oligonucleotides differ from those of small molecules. In addition, there are considerations regarding experimental approaches in the evaluation of oligonucleotides, such as bioanalytical challenges, the use of radiolabeled tracers, materials for metabolism/DDI studies, and methods to study biodistribution. In this review, we attempt to summarize the DMPK characteristics of antisense oligonucleotide (ASO) therapeutics and discuss some of the issues regarding how to optimize the evaluation and prediction of the DMPK and DDI of ASOs.
Topics: Oligonucleotides, Antisense; Pharmaceutical Preparations; Tissue Distribution; Oligonucleotides; Drug Delivery Systems
PubMed: 36735616
DOI: 10.1089/nat.2022.0054 -
JAMA Neurology Aug 2020An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping.
DESIGN, SETTING, AND PARTICIPANTS
This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019.
INTERVENTIONS
Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion.
MAIN OUTCOMES AND MEASURES
Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function.
RESULTS
Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.
CONCLUSIONS AND RELEVANCE
Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02740972.
Topics: Child; Child, Preschool; Double-Blind Method; Dystrophin; Exons; Humans; Male; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Outcome Assessment, Health Care
PubMed: 32453377
DOI: 10.1001/jamaneurol.2020.1264 -
Drugs Apr 2024Eplontersen (Wainua™) is a ligand-conjugated antisense oligonucleotide directed to TTR, which is being developed by Ionis Pharmaceuticals and AstraZeneca for the... (Review)
Review
Eplontersen (Wainua™) is a ligand-conjugated antisense oligonucleotide directed to TTR, which is being developed by Ionis Pharmaceuticals and AstraZeneca for the treatment of TTR-mediated amyloidosis (ATTR). Eplontersen, which is targeted to the liver by a ligand containing three N-acetyl galactosamine residues, binds to wild-type and variant TTR mRNA, thus reducing the levels of circulating TTR protein and amyloid deposition. Subcutaneous eplontersen reduced serum TTR levels, inhibited neuropathy progression and improved health-related quality of life in patients with polyneuropathy of hereditary ATTR (ATTRv-PN; v for variant) in a phase III trial. Based on these results, eplontersen was approved in the USA for the treatment of ATTRv-PN on 21 December 2023 and is currently undergoing regulatory review for a similar indication in the EU, the UK, Switzerland and Canada. Eplontersen is also undergoing phase III development for ATTR cardiomyopathy. This article summarizes the milestones in the development of eplontersen leading to this first approval for ATTRv-PN.
Topics: Humans; Amyloid Neuropathies, Familial; Prealbumin; Drug Approval; Oligonucleotides; Oligonucleotides, Antisense; Quality of Life; Clinical Trials, Phase III as Topic
PubMed: 38413492
DOI: 10.1007/s40265-024-02008-5 -
Nucleic Acid Therapeutics Oct 2023This white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working...
This white paper summarizes the recommendations of the absorption, distribution, metabolism, and excretion (ADME) Subcommittee of the Oligonucleotide Safety Working Group for the characterization of absorption, distribution, metabolism, and excretion of oligonucleotide (ON) therapeutics in nonclinical studies. In general, the recommended approach is similar to that for small molecule drugs. However, some differences in timing and/or scope may be warranted due to the greater consistency of results across ON classes as compared with the diversity among small molecule classes. For some types of studies, a platform-based approach may be appropriate; once sufficient data are available for the platform, presentation of these data should be sufficient to support development of additional ONs of the same platform. These recommendations can serve as a starting point for nonclinical study design and foundation for discussions with regulatory agencies.
Topics: Oligonucleotides
PubMed: 37590469
DOI: 10.1089/nat.2023.0011 -
Biosensors & Bioelectronics Mar 2023The growing use of aptamers as target recognition elements in label-free biosensing necessitates corresponding transducers that can be used in relevant environments.... (Review)
Review
The growing use of aptamers as target recognition elements in label-free biosensing necessitates corresponding transducers that can be used in relevant environments. While popular in many fields, capacitive sensors have seen relatively little, but growing use in conjunction with aptamers for sensing diverse targets. Few reports have shown physiologically relevant sensitivity in laboratory conditions and a cohesive picture on how target capture modifies the measured capacitance has been lacking. In this review, we assess the current state of the field in three areas: small molecule, protein, and cell sensing. We critically analyze the proposed hypotheses on how aptamer-target capture modifies the capacitance, as many mechanistic postulations appear to conflict between published works. As the field matures, we encourage future works to investigate individual aptamer-target interactions and to interrogate the physical mechanisms leading to measured changes in capacitance. To this point, we provide recommendations on best practices for developing aptasensors with a particular focus on considerations for biosensing in clinical settings.
Topics: Aptamers, Nucleotide; Biosensing Techniques; Transducers
PubMed: 36628826
DOI: 10.1016/j.bios.2022.115014 -
Muscle & Nerve Sep 2021Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, tolerability, and pharmacokinetics of casimersen in patients with Duchenne muscular dystrophy amenable to exon 45 skipping: A randomized, double-blind, placebo-controlled, dose-titration trial.
INTRODUCTION/AIMS
Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene resulting in the absence of dystrophin. Casimersen is a phosphorodiamidate morpholino oligomer designed to bypass frameshift DMD mutations and produce internally truncated, yet functional, dystrophin protein in patients amenable to exon 45 skipping. Our primary study objective was to evaluate safety and tolerability of casimersen; the secondary objective was to characterize the plasma pharmacokinetics.
METHODS
This multicenter, phase 1/2 trial enrolled 12 participants (aged 7-21 years, who had limited ambulation or were nonambulatory) and comprised a 12-week, double-blind dose titration, then an open-label extension for up to 132 weeks. During dose titration, participants were randomized 2:1 to weekly casimersen infusions at escalating doses of 4, 10, 20, and 30 mg/kg (≥2 weeks per dose), or placebo.
RESULTS
Participants received casimersen for a mean 139.6 weeks. Treatment-emergent adverse events (TEAEs) occurred in all casimersen- and placebo-treated participants and were mostly mild (over 91.4%) and unrelated to casimersen or its dose. There were no deaths, dose reductions, abnormalities in laboratory parameters or vital signs, or casimersen-related serious AEs. Casimersen plasma concentration increased with dose and declined similarly for all dose levels over 24 hours postinfusion. All pharmacokinetic parameters were similar at weeks 7 and 60.
DISCUSSION
Casimersen was well tolerated in participants with DMD amenable to exon 45 skipping. Most TEAEs were mild, nonserious, and unrelated to casimersen. Plasma exposure was dose proportional with no suggestion of plasma accumulation. These results support further studies of casimersen in this population.
Topics: Adolescent; Child; Double-Blind Method; Dystrophin; Exons; Humans; Male; Muscular Dystrophy, Duchenne; Mutation; Oligonucleotides; Young Adult
PubMed: 34105177
DOI: 10.1002/mus.27347 -
Biomolecules Oct 2022Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader... (Review)
Review
Nucleic acids and proteins form two of the key classes of functional biomolecules. Through the ability to access specific protein-oligonucleotide conjugates, a broader range of functional molecules becomes accessible which leverages both the programmability and recognition potential of nucleic acids and the structural, chemical and functional diversity of proteins. Herein, we summarize the available conjugation strategies to access such chimeric molecules and highlight some key case study examples within the field to showcase the power and utility of such technology.
Topics: Oligonucleotides; Nucleic Acids; Proteins
PubMed: 36291732
DOI: 10.3390/biom12101523 -
European Heart Journal Nov 2022Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense... (Review)
Review
Novel bio-therapeutic agents that harness the properties of small, non-coding nucleic acids hold great promise for clinical applications. These include antisense oligonucleotides that inhibit messenger RNAs, microRNAs (miRNAs), or long non-coding RNAs; positive effectors of the miRNA pathway (short interfering RNAs and miRNA mimics); or small RNAs that target proteins (i.e. aptamers). These new therapies also offer exciting opportunities for cardiovascular diseases and promise to move the field towards more precise approaches based on disease mechanisms. There have been substantial advances in developing chemical modifications to improve the in vivo pharmacological properties of antisense oligonucleotides and reduce their immunogenicity. Carrier methods (e.g. RNA conjugates, polymers, and lipoplexes) that enhance cellular uptake of RNA therapeutics and stability against degradation by intracellular nucleases are also transforming the field. A number of small non-coding RNA therapies for cardiovascular indications are now approved. Moreover, there is a large pipeline of therapies in clinical development and an even larger list of putative therapies emerging from pre-clinical studies. Progress in this area is reviewed herein along with the hurdles that need to be overcome to allow a broader clinical translation.
Topics: Humans; Cardiovascular Diseases; Oligonucleotides, Antisense; MicroRNAs; RNA, Small Interfering; Oligonucleotides
PubMed: 36106499
DOI: 10.1093/eurheartj/ehac463 -
Molecules (Basel, Switzerland) Dec 2022The hemostasis system is a complex structure that includes the fibrinolysis system, and Yes this is correct coagulation and anticoagulation parts. Due to the... (Review)
Review
The hemostasis system is a complex structure that includes the fibrinolysis system, and Yes this is correct coagulation and anticoagulation parts. Due to the multicomponent nature, it becomes relevant to study the key changes in the functioning of signaling pathways, and develop new diagnostic methods and modern drugs with high selectivity. One of the ways to solve this problem is the development of molecular recognition elements capable of blocking one of the hemostasis systems and/or activating another. Aptamers can serve as ligands for targeting specific clinical needs, promising anticoagulants with minor side effects and significant biological activity. Aptamers with several clotting factors and platelet proteins are used for the treatment of thrombosis. This review is focused on the aptamers used for the correction of the hemostasis system, and their structural and functional features. G-rich nucleic acid aptamers, mostly versatile G-quadruplexes, recognize different components of the hemostasis system and are capable of correcting the functioning.
Topics: Aptamers, Nucleotide; Hemostasis; Blood Coagulation; G-Quadruplexes; Anticoagulants; Blood Platelets
PubMed: 36500686
DOI: 10.3390/molecules27238593 -
Neuropharmacology Nov 2021RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such... (Review)
Review
RNA aptamers are single-stranded RNA molecules, and they are selected against a target of interest so that they can bind to and modulate the activity of the target, such as inhibiting the target activity, with high potency and selectivity. Antagonists, such as RNA aptamers, acting on AMPA receptors, a major subtype of ionotropic glutamate receptors, are potential drug candidates for treatment of a number of CNS diseases that involve excessive receptor activation and/or elevated receptor expression. Here we review the approach to discover RNA aptamers targeting AMPA receptors from a random sequence library (∼10 sequences) through a process called systematic evolution of ligands by exponential enrichment (SELEX). As compared with small-molecule compounds, RNA aptamers are a new class of regulatory agents with interesting and desirable pharmacological properties. Some AMPA receptor aptamers we have developed are presented in this review. The promises and challenges of translating RNA aptamers into potential drugs and treatment options are also discussed. This article is part of the special Issue on 'Glutamate Receptors - AMPA receptors'.
Topics: Animals; Aptamers, Nucleotide; Central Nervous System Diseases; Humans; Receptors, AMPA
PubMed: 34509496
DOI: 10.1016/j.neuropharm.2021.108761