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Advanced Drug Delivery Reviews Nov 2021Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize... (Review)
Review
Recent medical advances have exploited the ability to address a given disease at the underlying level of transcription and translation. These treatment paradigms utilize nucleic acids - including short interfering RNA (siRNA), microRNA (miRNA), antisense oligonucleotides (ASO), and messenger RNA (mRNA) - to achieve a desired outcome ranging from gene knockdown to induced expression of a selected target protein. Towards this end, numerous strategies for encapsulation or stabilization of various nucleic acid structures have been developed in order to achieve intracellular delivery. In this review, we discuss several therapeutic applications of nucleic acids directed towards specific diseases and tissues of interest, in particular highlighting recent technologies which have reached late-stage clinical trials and received FDA approval.
Topics: Animals; COVID-19; Clinical Trials as Topic; Drug Approval; Drug Delivery Systems; Gene Transfer Techniques; Hepatitis; Humans; MicroRNAs; Neoplasms; Nucleic Acids; Oligonucleotides, Antisense; RNA, Messenger; RNA, Small Interfering
PubMed: 34492233
DOI: 10.1016/j.addr.2021.113834 -
BMJ (Clinical Research Ed.) May 2019Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic... (Review)
Review
Sensory polyneuropathies, which are caused by dysfunction of peripheral sensory nerve fibers, are a heterogeneous group of disorders that range from the common diabetic neuropathy to the rare sensory neuronopathies. The presenting symptoms, acuity, time course, severity, and subsequent morbidity vary and depend on the type of fiber that is affected and the underlying cause. Damage to small thinly myelinated and unmyelinated nerve fibers results in neuropathic pain, whereas damage to large myelinated sensory afferents results in proprioceptive deficits and ataxia. The causes of these disorders are diverse and include metabolic, toxic, infectious, inflammatory, autoimmune, and genetic conditions. Idiopathic sensory polyneuropathies are common although they should be considered a diagnosis of exclusion. The diagnostic evaluation involves electrophysiologic testing including nerve conduction studies, histopathologic analysis of nerve tissue, serum studies, and sometimes autonomic testing and cerebrospinal fluid analysis. The treatment of these diseases depends on the underlying cause and may include immunotherapy, mitigation of risk factors, symptomatic treatment, and gene therapy, such as the recently developed RNA interference and antisense oligonucleotide therapies for transthyretin familial amyloid polyneuropathy. Many of these disorders have no directed treatment, in which case management remains symptomatic and supportive. More research is needed into the underlying pathophysiology of nerve damage in these polyneuropathies to guide advances in treatment.
Topics: Complementary Therapies; Genetic Therapy; Humans; Immunotherapy; Meta-Analysis as Topic; Nerve Fibers, Myelinated; Nerve Fibers, Unmyelinated; Neurologic Examination; Observational Studies as Topic; Polyneuropathies; Randomized Controlled Trials as Topic; Risk Reduction Behavior; Sensory Thresholds
PubMed: 31068323
DOI: 10.1136/bmj.l1108 -
Biomolecules Aug 2021Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for... (Review)
Review
Despite being the most prevalent cause of inherited blindness in children, Stargardt disease is yet to achieve the same clinical trial success as has been achieved for other inherited retinal diseases. With an early age of onset and continual progression of disease over the life course of an individual, Stargardt disease appears to lend itself to therapeutic intervention. However, the aetiology provides issues not encountered with the likes of choroideremia and X-linked retinitis pigmentosa and this has led to a spectrum of treatment strategies that approach the problem from different aspects. These include therapeutics ranging from small molecules and anti-sense oligonucleotides to viral gene supplementation and cell replacement. The advancing development of CRISPR-based molecular tools is also likely to contribute to future therapies by way of genome editing. In this we review, we consider the most recent pre-clinical and clinical trial data relating to the different strategies being applied to the problem of generating a treatment for the large cohort of Stargardt disease patients worldwide.
Topics: Animals; Cell Line; Child; Clinical Trials as Topic; Gene Editing; Genetic Therapy; Humans; Mice; Stargardt Disease
PubMed: 34439845
DOI: 10.3390/biom11081179 -
Current Gene Therapy 2022This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye, including cornea, conjunctiva, lacrimal gland, and... (Review)
Review
This review provides comprehensive information about the advances in gene therapy in the anterior segment of the eye, including cornea, conjunctiva, lacrimal gland, and trabecular meshwork. We discuss gene delivery systems, including viral and non-viral vectors as well as gene editing techniques, mainly CRISPR-Cas9, and epigenetic treatments, including antisense and siRNA therapeutics. We also provide a detailed analysis of various anterior segment diseases where gene therapy has been tested with corresponding outcomes. Disease conditions include corneal and conjunctival fibrosis and scarring, corneal epithelial wound healing, corneal graft survival, corneal neovascularization, genetic corneal dystrophies, herpetic keratitis, glaucoma, dry eye disease, and other ocular surface diseases. Although most of the analyzed results on the use and validity of gene therapy at the ocular surface have been obtained in vitro or using animal models, we also discuss the available human studies. Gene therapy approaches are currently considered very promising as emerging future treatments of various diseases, and this field is rapidly expanding.
Topics: Animals; Anterior Eye Segment; Cornea; Gene Editing; Gene Transfer Techniques; Genetic Therapy
PubMed: 33902406
DOI: 10.2174/1566523221666210423084233 -
Journal of Neuromuscular Diseases 2020Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum... (Review)
Review
Spinal Muscular Atrophy (SMA) is caused by autosomal recessive mutations in SMN1 and results in the loss of motor neurons and progressive muscle weakness. The spectrum of disease severity ranges from early onset with respiratory failure during the first months of life to a mild, adult-onset type with slow rate of progression. Over the past decade, new treatment options such as splicing modulation of SMN2 and SMN1 gene replacement by gene therapy have been developed. First drugs have been approved for treatment of patients with SMA and if initiated early they can significantly modify the natural course of the disease. As a consequence, newborn screening for SMA is explored and implemented in an increasing number of countries. However, available evidence for these new treatments is often limited to a small spectrum of patients concerning age and disease stage. In this review we provide an overview of available and emerging therapies for spinal muscular atrophy and we discuss new phenotypes and associated challenges in clinical care. Collection of real-world data with standardized outcome measures will be essential to improve both the understanding of treatment effects in patients of all SMA subtypes and the basis for clinical decision-making in SMA.
Topics: Genetic Therapy; Humans; Infant, Newborn; Muscular Atrophy, Spinal; Neonatal Screening; Oligonucleotides, Antisense; Thionucleotides
PubMed: 31707373
DOI: 10.3233/JND-190424 -
Muscle & Nerve Feb 2015Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form... (Review)
Review
Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q-SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produces reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early-phase clinical trials.
Topics: DNA, Antisense; Electromyography; Genetic Therapy; Humans; Muscular Atrophy, Spinal; Survival of Motor Neuron 1 Protein
PubMed: 25346245
DOI: 10.1002/mus.24497 -
The EMBO Journal Nov 2023RNA-based therapeutics have the potential to revolutionize the treatment and prevention of human diseases. While early research faced setbacks, it established the basis... (Review)
Review
RNA-based therapeutics have the potential to revolutionize the treatment and prevention of human diseases. While early research faced setbacks, it established the basis for breakthroughs in RNA-based drug design that culminated in the extraordinarily fast development of mRNA vaccines to combat the COVID-19 pandemic. We have now reached a pivotal moment where RNA medicines are poised to make a broad impact in the clinic. In this review, we present an overview of different RNA-based strategies to generate novel therapeutics, including antisense and RNAi-based mechanisms, mRNA-based approaches, and CRISPR-Cas-mediated genome editing. Using three rare genetic diseases as examples, we highlight the opportunities, but also the challenges to wide-ranging applications of this class of drugs.
Topics: Humans; RNA; Pandemics; Gene Editing; RNA Interference; Genetic Therapy
PubMed: 37728251
DOI: 10.15252/embj.2023114760 -
Neuron Mar 2019Huntington's disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant... (Review)
Review
Huntington's disease is caused by an abnormally expanded CAG repeat expansion in the HTT gene, which confers a predominant toxic gain of function in the mutant huntingtin (mHTT) protein. There are currently no disease-modifying therapies available, but approaches that target proximally in disease pathogenesis hold great promise. These include DNA-targeting techniques such as zinc-finger proteins, transcription activator-like effector nucleases, and CRISPR/Cas9; post-transcriptional huntingtin-lowering approaches such as RNAi, antisense oligonucleotides, and small-molecule splicing modulators; and novel methods to clear the mHTT protein, such as proteolysis-targeting chimeras. Improvements in the delivery and distribution of such agents as well as the development of objective biomarkers of disease and of HTT lowering pharmacodynamic outcomes have brought these potential therapies to the forefront of Huntington's disease research, with clinical trials in patients already underway.
Topics: Animals; CRISPR-Cas Systems; Genetic Therapy; Humans; Huntingtin Protein; Huntington Disease
PubMed: 30844400
DOI: 10.1016/j.neuron.2019.01.039 -
Annual Review of Medicine Jan 2019The first published description of therapeutic applications of antisense oligonucleotide (ASO) technology occurred in the late 1970s and was followed by the founding of... (Review)
Review
The first published description of therapeutic applications of antisense oligonucleotide (ASO) technology occurred in the late 1970s and was followed by the founding of commercial companies focused on developing antisense therapeutics in the late 1980s. Since the late 1980s, there has been steady progress in improving the technology platform, taking advantage of advances in oligonucleotide chemistry and formulations as well as increased understanding of the distribution and safety of ASOs. There are several approved ASO drugs and a broad pipeline in development. In addition, advances in understanding human disease, including the genetic basis for most monogenic diseases and the availability of the full human genome sequence, have created numerous therapeutic applications for the technology. I summarize the state of the technology and highlight how advances in the technology position ASOs to be an important contributor to future medicines.
Topics: Clinical Trials, Phase I as Topic; Female; Forecasting; Genome, Human; Humans; Male; Molecular Targeted Therapy; Oligonucleotides; Oligonucleotides, Antisense; Patient Safety; Pharmacogenetics; Risk Assessment
PubMed: 30691367
DOI: 10.1146/annurev-med-041217-010829 -
Science China. Life Sciences Jan 2023Recent advancements in the production, modification, and cellular delivery of RNA molecules facilitated the expansion of RNA-based therapeutics. The increasing... (Review)
Review
Recent advancements in the production, modification, and cellular delivery of RNA molecules facilitated the expansion of RNA-based therapeutics. The increasing understanding of RNA biology initiated a corresponding growth in RNA therapeutics. In this review, the general concepts of five classes of RNA-based therapeutics, including RNA interference-based therapies, antisense oligonucleotides, small activating RNA therapies, circular RNA therapies, and messenger RNA-based therapeutics, will be discussed. Moreover, we also provide an overview of RNA-based therapeutics that have already received regulatory approval or are currently being evaluated in clinical trials, along with challenges faced by these technologies. RNA-based drugs demonstrated positive clinical trial results and have the ability to address previously "undruggable" targets, which delivers great promise as a disruptive therapeutic technology to fulfill its full clinical potentiality.
Topics: RNA, Small Interfering; RNA Interference; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 36100838
DOI: 10.1007/s11427-022-2171-2