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Current Opinion in Lipidology Dec 2018To summarize recent developments in the field of RNA-directed therapeutics targeting lipid disorders that are not effectively managed. (Review)
Review
PURPOSE OF REVIEW
To summarize recent developments in the field of RNA-directed therapeutics targeting lipid disorders that are not effectively managed.
RECENT FINDINGS
Despite a number of approved therapies for lipid disorders, significant unmet needs are present in treating persistently elevated LDL-cholesterol, remnant-cholesterol, triglycerides and lipoprotein(a) [Lp(a)]. Small molecules and antibodies are effective modalities, but they are unable to adequately treat many patients with abnormal lipid parameters. Targeting mRNA with oligonucleotides to prevent protein translation is a relatively novel method to reduce circulating atherogenic lipoproteins. Small inhibiting RNA (siRNA) molecules targeting proprotein convertase subtilisin kexin type 9 to reduce LDL-C, and antisense oligonucleotides (ASO) targeting apolipoprotein C-III (apoC-III) to reduce triglycerides, angiopoietin-like 3 (ANGPTL3) to reduce LDL-C and triglycerides and apolipoprotein(a) (LPA) to reduce Lp(a) are currently in or just completed phase 1-3 trials. Fundamental differences exist in chemistry, delivery and mechanism of action of siRNA and ASOs.
SUMMARY
Novel RNA therapeutics are poised to provide highly potent, specific and effective therapies to reduce atherogenic lipoproteins. As these compounds are approved, clinicians will be able to choose from a broad armamentarium to treat nearly all patients to acceptable goals in order to reduce risk of cardiovascular disease and events.
Topics: Humans; Lipid Metabolism Disorders; Molecular Targeted Therapy; RNA
PubMed: 30234555
DOI: 10.1097/MOL.0000000000000549 -
Current Opinion in Oncology Nov 2014Over the past several dozen years, regardless of the substantial effort directed toward developing rational oligonucleotide strategies to silence gene expression,... (Review)
Review
PURPOSE OF REVIEW
Over the past several dozen years, regardless of the substantial effort directed toward developing rational oligonucleotide strategies to silence gene expression, antisense oligonucleotide-based cancer therapy has not been successful. This review focuses on the most likely reasons for this lack of success, and on the barriers that still need to be overcome to make a clinical cancer treatment reality out of the promise of antisense therapy.
RECENT FINDINGS
Considerable progress has been made in the design and delivery of nucleic acid fragments. Chemical modifications have considerably improved oligonucleotide absorption, distribution and metabolism while at the same time reducing toxicity. Nevertheless, the delivery and the cellular uptake of these molecules are still not adequate to provide the desired therapeutic outcome. Recent therapeutic interventional phase III trials of antisense oligodeoxyribonucleotides for a cancer indication will be discussed, in addition to those studies that markedly improve the scientific understanding of the properties of these molecules.
SUMMARY
We still do not have a marketed antisense oligonucleotide for a cancer indication. This is because critical aspects of the cellular, tumor pharmacology and delivery properties of these agents are still not well understood.
Topics: Animals; Genetic Therapy; Humans; Neoplasms; Oligonucleotides, Antisense
PubMed: 25188471
DOI: 10.1097/CCO.0000000000000127 -
Revue Neurologique 2023Familial ALS (FALS) accounts for 10 to 15% of ALS cases. In more than 70% of FALS patients, a causal gene is identified and animal models have been developed for a... (Review)
Review
Familial ALS (FALS) accounts for 10 to 15% of ALS cases. In more than 70% of FALS patients, a causal gene is identified and animal models have been developed for a subset of them, mainly for the most frequently mutated genes. Therapeutic tools to treat those patients are dominated by gene-specific therapy and the most advanced approaches target the SOD1 gene mutations. Either by direct delivery of antisense oligonucleotides (ASO) or using viral vectors such as adenoviruses (AAV) to deliver ASOs, gene specific therapies have shown promising results in animal models. The recent use of subpial injections of AAV9+anti SOD1 ASO now shows that the disease is completely prevented or stopped in the animal, depending on the moment of injection, e.g., before or after disease onset. However, the use of viral vectors in humans seems to be limited at least by their immunogenicity. Antibody-based therapies are also efficient to treat animal models, but to a lesser extent. Most of the experiments targeted the SOD1 protein in its misfolded conformation. This approach seems better tolerated than the AAV one, an important limit being the choice of the epitope. Unexpectedly, some advances in treating the C9ORF72 animal model have been obtained using a modulation of microbiota, and this strategy has the great advantage to have an easy route of administration and a good safety profile. The landscape of experimental FALS treatment is rapidly evolving and results are promising. This is an important unmet need for ALS patients and several human phase I, II and III trials are ongoing.
Topics: Animals; Humans; Amyotrophic Lateral Sclerosis; Superoxide Dismutase-1; Mutation; Oligonucleotides, Antisense; Genetic Therapy
PubMed: 36503675
DOI: 10.1016/j.neurol.2022.10.001 -
Expert Opinion on Biological Therapy May 2021In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered... (Review)
Review
INTRODUCTION
In the retina, noncoding RNA (ncRNA) plays an integral role in regulating apoptosis, inflammatory responses, visual perception, and photo-transduction, with altered levels reported in diseased states.
AREAS COVERED
MicroRNA (miRNA), a class of ncRNA, regulates post-transcription gene expression through the binding of complementary sites of target messenger RNA (mRNA) with resulting translational repression. Small-interfering RNA (siRNA) is a double-stranded RNA (dsRNA) that regulates gene expression, leading to selective silencing of genes through a process called RNA interference (RNAi). Another form of RNAi involves short hairpin RNA (shRNA). In age-related macular degeneration (AMD) and diabetic retinopathy (DR), miRNA has been implicated in the regulation of angiogenesis, oxidative stress, immune response, and inflammation.
EXPERT OPINION
Many RNA-based therapies in development are conveniently administered intravitreally, with the potential for pan-retinal effect. The majority of these RNA therapeutics are synthetic ncRNA's and hold promise for the treatment of AMD, DR, and inherited retinal diseases (IRDs). These RNA-based therapies include siRNA therapy with its high specificity, shRNA to 'knock down' autosomal dominant toxic gain of function-mutated genes, antisense oligonucleotides (ASOs), which can restore splicing defects, and translational read-through inducing drugs (TRIDs) to increase expression of full-length protein from genes with premature stop codons.
Topics: Humans; MicroRNAs; Oligonucleotides, Antisense; RNA Interference; RNA, Small Interfering; Retinal Diseases
PubMed: 33307874
DOI: 10.1080/14712598.2021.1856365 -
Current Opinion in Neurology Oct 2022The development of new therapies has brought spinal muscular atrophy (SMA) into the spotlight. However, this was preceded by a long journey - from the first clinical... (Review)
Review
PURPOSE OF REVIEW
The development of new therapies has brought spinal muscular atrophy (SMA) into the spotlight. However, this was preceded by a long journey - from the first clinical description to the discovery of the genetic cause to molecular mechanisms of RNA and DNA technology.
RECENT FINDINGS
Since 2016, the antisense oligonucleotide nusinersen has been (FDA) approved for the treatment of SMA, followed by the gene replacement therapy onasemnogene abeparvovec-xioi in 2019 and the small-molecule risdiplam in 2020. These drugs, all targeting upregulation of the SMN protein not only showed remarkable effects in clinical trials but also in real-world settings. SMA has been implemented in newborn screening in many countries around the world. SMN-independent strategies targeting skeletal muscle, for example, may play another therapeutic approach in the future.
SUMMARY
This review aims to summarize the major clinical and basic science achievements in the field of SMA.
Topics: Genetic Therapy; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Oligonucleotides, Antisense
PubMed: 35942665
DOI: 10.1097/WCO.0000000000001102 -
Nature Reviews. Drug Discovery Jun 2022Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design... (Review)
Review
Recent years have seen unprecedented activity in the development of RNA-silencing oligonucleotide therapeutics for metabolic diseases. Improved oligonucleotide design and optimization of synthetic nucleic acid chemistry, in combination with the development of highly selective and efficient conjugate delivery technology platforms, have established and validated oligonucleotides as a new class of drugs. To date, there are five marketed oligonucleotide therapies, with many more in clinical studies, for both rare and common liver-driven metabolic diseases. Here, we provide an overview of recent developments in the field of oligonucleotide therapeutics in metabolism, review past and current clinical trials, and discuss ongoing challenges and possible future developments.
Topics: Humans; Metabolic Diseases; Oligonucleotides; Oligonucleotides, Antisense; RNA; RNA Interference
PubMed: 35210608
DOI: 10.1038/s41573-022-00407-5 -
Expert Review of Neurotherapeutics 2023Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder caused by insufficiency or total absence of the survival motor neuron protein due to a mutation... (Review)
Review
INTRODUCTION
Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder caused by insufficiency or total absence of the survival motor neuron protein due to a mutation in the gene. The copy number of its paralog, , influences disease onset and phenotype severity. Current therapeutic approaches include viral and non-viral modalities affecting gene expression. Regulatory-approved drugs Spinraza (Nusinersen), Zolgensma (Onasemnogene abeparvovec), and Evrysdi (Risdiplam) are still being investigated during clinical trials and show benefits in the long-term for symptomatic and pre-symptomatic patients. However, some ongoing interventions require repeated drug administration.
AREAS COVERED
In this review, the authors describe the existing therapy based on point of application, focusing on recent clinical trials of antisense oligonucleotides, viral gene therapy, and splice modulators and thepotential routes for correcting the mutation to provide therapeutic levels of SMN protein.
EXPERT OPINION
In the opinion of the authors, multiple treatment options for patients with SMA shifted the treatment paradigm from palliative supportive care to improvedmotor function, increased survival, and greater quality of life for such patients. They further believe that the future in SMA treatment development lies incombining existing treatment options, targeting aspects of the disease refractory to these treatments, and using gene editing technologies.
Topics: Humans; Quality of Life; Muscular Atrophy, Spinal; Oligonucleotides, Antisense; Genetic Therapy; Mutation
PubMed: 37843301
DOI: 10.1080/14737175.2023.2268276 -
Molecules (Basel, Switzerland) Apr 2017Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness... (Review)
Review
Neuromuscular disorders such as Duchenne Muscular Dystrophy and Spinal Muscular Atrophy are neurodegenerative genetic diseases characterized primarily by muscle weakness and wasting. Until recently there were no effective therapies for these conditions, but antisense oligonucleotides, a new class of synthetic single stranded molecules of nucleic acids, have demonstrated promising experimental results and are at different stages of regulatory approval. The antisense oligonucleotides can modulate the protein expression via targeting hnRNAs or mRNAs and inducing interference with splicing, mRNA degradation, or arrest of translation, finally, resulting in rescue or reduction of the target protein expression. Different classes of antisense oligonucleotides are being tested in several clinical trials, and limitations of their clinical efficacy and toxicity have been reported for some of these compounds, while more encouraging results have supported the development of others. New generation antisense oligonucleotides are also being tested in preclinical models together with specific delivery systems that could allow some of the limitations of current antisense oligonucleotides to be overcome, to improve the cell penetration, to achieve more robust target engagement, and hopefully also be associated with acceptable toxicity. This review article describes the chemical properties and molecular mechanisms of action of the antisense oligonucleotides and the therapeutic implications these compounds have in neuromuscular diseases. Current strategies and carrier systems available for the oligonucleotides delivery will be also described to provide an overview on the past, present and future of these appealing molecules.
Topics: Animals; Biological Transport; Cell-Penetrating Peptides; Clinical Trials as Topic; Drug Evaluation, Preclinical; Gene Transfer Techniques; Genetic Therapy; Humans; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Neuromuscular Diseases; Oligonucleotides, Antisense; RNA Splicing; RNA, Messenger
PubMed: 28379182
DOI: 10.3390/molecules22040563 -
Current Opinion in Genetics &... Dec 2020Nucleic acid therapeutics allow sequence-based targeting of mutation-harboring genes. They can be used to increase the expression and function of disease genes or to... (Review)
Review
Nucleic acid therapeutics allow sequence-based targeting of mutation-harboring genes. They can be used to increase the expression and function of disease genes or to decrease the expression of toxic gene products. Antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), and gene-replacement therapies have received FDA approval, and in vivo gene editing applications are currently under development. Special consideration should be given to target engagement in neurons and amelioration of neurological phenotypes. Here we discuss the uses and limitations of different nucleic acid therapeutics, highlighting examples in the clinical and pre-clinical application of these modalities for the treatment of neurodevelopmental diseases.
Topics: Animals; Gene Editing; Genetic Therapy; Humans; Neurodevelopmental Disorders; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 32623324
DOI: 10.1016/j.gde.2020.05.022 -
Practical Neurology Apr 2018Many genetic neurological diseases result from the dysfunction of single proteins. Genetic therapies aim to modify these disease-associated proteins by targeting the RNA... (Review)
Review
Many genetic neurological diseases result from the dysfunction of single proteins. Genetic therapies aim to modify these disease-associated proteins by targeting the RNA and DNA precursors. This review provides a brief overview of the main types of genetic therapies, with a focus on antisense oligonucleotides (ASOs) and RNA interference (RNAi). We use examples of new genetic therapies for spinal muscular atrophy, Duchenne muscular dystrophy and familial amyloid polyneuropathy to highlight the different mechanisms of action of ASOs and RNAi.
Topics: Genetic Therapy; Humans; Oligodeoxyribonucleotides, Antisense; RNA Interference
PubMed: 29455156
DOI: 10.1136/practneurol-2017-001764