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Expert Review of Anti-infective Therapy Dec 2020Coronavirus disease 2019 (COVID-19) was first detected in China in December, 2019, and declared as a pandemic by the World Health Organization (WHO) on March 11, 2020.... (Review)
Review
INTRODUCTION
Coronavirus disease 2019 (COVID-19) was first detected in China in December, 2019, and declared as a pandemic by the World Health Organization (WHO) on March 11, 2020. The current management of COVID-19 is based generally on supportive therapy and treatment to prevent respiratory failure. The effective option of antiviral therapy and vaccination are currently under evaluation and development.
AREAS COVERED
A literature search was performed using PubMed between December 1, 2019-June 23, 2020. This review highlights the current state of knowledge on the viral replication and pathogenicity, diagnostic and therapeutic strategies, and management of COVID-19. This review will be of interest to scientists and clinicians and make a significant contribution toward development of vaccines and targeted therapies to contain the pandemic.
EXPERT OPINION
The exit strategy for a path back to normal life is required, which should involve a multi-prong effort toward development of new treatment and a successful vaccine to protect public health worldwide and prevent future COVID-19 outbreaks. Therefore, the bench to bedside translational research as well as reverse translational works focusing bedside to bench is very important and would provide the foundation for the development of targeted drugs and vaccines for COVID-19 infections.
Topics: Anticoagulants; Antimalarials; Antiviral Agents; COVID-19; COVID-19 Nucleic Acid Testing; COVID-19 Serological Testing; COVID-19 Testing; Drug Development; Hospice Care; Humans; Immunization, Passive; Life Support Care; Oligonucleotides, Antisense; Palliative Care; RNA, Antisense; SARS-CoV-2; COVID-19 Drug Treatment; COVID-19 Serotherapy
PubMed: 32749914
DOI: 10.1080/14787210.2020.1797487 -
Molecular Therapy : the Journal of the... Dec 2021Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the... (Review)
Review
Amyotrophic lateral sclerosis (ALS) has historically posed unique challenges for gene-therapy-based approaches, due to a paucity of therapeutic targets as well as the difficulty of accessing both the brain and spinal cord. Recent advances in our understanding of disease mechanism and ALS genetics, however, have combined with tremendous strides in CNS targeting, gene delivery, and gene editing and knockdown techniques to open new horizons of therapeutic possibility. Gene therapy clinical trials are currently underway for ALS patients with SOD1 mutations, C9orf72 hexanucleotide repeat expansions, ATXN2 trinucleotide expansions, and FUS mutations, as well as sporadic disease without known genetic cause. In this review, we provide an in-depth exploration of the state of ALS-directed gene therapy, including antisense oligonucleotides, RNA interference, CRISPR, adeno-associated virus (AAV)-mediated trophic support, and antibody-based methods. We discuss how each of these approaches has been implemented across known genetic causes as well as sporadic ALS, reviewing preclinical studies as well as completed and ongoing human clinical trials. We highlight the transformative potential of these evolving technologies as the gene therapy field advances toward a true disease-modifying treatment for this devastating illness.
Topics: Amyotrophic Lateral Sclerosis; C9orf72 Protein; Dependovirus; Genetic Therapy; Humans; Oligonucleotides, Antisense
PubMed: 33839324
DOI: 10.1016/j.ymthe.2021.04.008 -
Cell Metabolism Apr 2018RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding... (Review)
Review
RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform.
Topics: Animals; Drug Discovery; Genetic Therapy; Humans; Molecular Targeted Therapy; Muscular Atrophy, Spinal; Oligoribonucleotides, Antisense; RNA, Small Interfering
PubMed: 29617640
DOI: 10.1016/j.cmet.2018.03.004 -
The Lancet. Neurology Jul 2022Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this... (Review)
Review
Huntington's disease is the most frequent autosomal dominant neurodegenerative disorder; however, no disease-modifying interventions are available for patients with this disease. The molecular pathogenesis of Huntington's disease is complex, with toxicity that arises from full-length expanded huntingtin and N-terminal fragments of huntingtin, which are both prone to misfolding due to proteolysis; aberrant intron-1 splicing of the HTT gene; and somatic expansion of the CAG repeat in the HTT gene. Potential interventions for Huntington's disease include therapies targeting huntingtin DNA and RNA, clearance of huntingtin protein, DNA repair pathways, and other treatment strategies targeting inflammation and cell replacement. The early termination of trials of the antisense oligonucleotide tominersen suggest that it is time to reflect on lessons learned, where the field stands now, and the challenges and opportunities for the future.
Topics: Humans; Huntingtin Protein; Huntington Disease; Neurodegenerative Diseases; Oligonucleotides; Oligonucleotides, Antisense; RNA Splicing
PubMed: 35716694
DOI: 10.1016/S1474-4422(22)00121-1 -
Nature Reviews. Drug Discovery Nov 2023Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most... (Review)
Review
Duchenne muscular dystrophy (DMD) is a monogenic muscle-wasting disorder and a priority candidate for molecular and cellular therapeutics. Although rare, it is the most common inherited myopathy affecting children and so has been the focus of intense research activity. It is caused by mutations that disrupt production of the dystrophin protein, and a plethora of drug development approaches are under way that aim to restore dystrophin function, including exon skipping, stop codon readthrough, gene replacement, cell therapy and gene editing. These efforts have led to the clinical approval of four exon skipping antisense oligonucleotides, one stop codon readthrough drug and one gene therapy product, with other approvals likely soon. Here, we discuss the latest therapeutic strategies that are under development and being deployed to treat DMD. Lessons from these drug development programmes are likely to have a major impact on the DMD field, but also on molecular and cellular medicine more generally. Thus, DMD is a pioneer disease at the forefront of future drug discovery efforts, with these experimental treatments paving the way for therapies using similar mechanisms of action being developed for other genetic diseases.
Topics: Child; Humans; Muscular Dystrophy, Duchenne; Dystrophin; Codon, Terminator; Oligonucleotides, Antisense; Mutation
PubMed: 37652974
DOI: 10.1038/s41573-023-00775-6 -
Nature Reviews. Drug Discovery Aug 2021Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of... (Review)
Review
Therapeutic targeting of noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), represents an attractive approach for the treatment of cancers, as well as many other diseases. Over the past decade, substantial effort has been made towards the clinical application of RNA-based therapeutics, employing mostly antisense oligonucleotides and small interfering RNAs, with several gaining FDA approval. However, trial results have so far been ambivalent, with some studies reporting potent effects whereas others demonstrated limited efficacy or toxicity. Alternative entities such as antimiRNAs are undergoing clinical testing, and lncRNA-based therapeutics are gaining interest. In this Perspective, we discuss key challenges facing ncRNA therapeutics - including issues associated with specificity, delivery and tolerability - and focus on promising emerging approaches that aim to boost their success.
Topics: Animals; Genetic Therapy; Humans; Molecular Targeted Therapy; Neoplasms; RNA, Long Noncoding
PubMed: 34145432
DOI: 10.1038/s41573-021-00219-z -
International Journal of Molecular... May 2020Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis... (Review)
Review
Since the early days of its conceptualization and application, human gene transfer held the promise of a permanent solution to genetic diseases including cystic fibrosis (CF). This field went through alternated periods of enthusiasm and distrust. The development of refined technologies allowing site specific modification with programmable nucleases highly revived the gene therapy field. CRISPR nucleases and derived technologies tremendously facilitate genome manipulation offering diversified strategies to reverse mutations. Here we discuss the advancement of gene therapy, from therapeutic nucleic acids to genome editing techniques, designed to reverse genetic defects in CF. We provide a roadmap through technologies and strategies tailored to correct different types of mutations in the cystic fibrosis transmembrane regulator ( gene, and their applications for the development of experimental models valuable for the advancement of CF therapies.
Topics: Animals; CRISPR-Cas Systems; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Disease Models, Animal; Gene Editing; Genetic Therapy; Genome, Human; Humans; Mice; Mutation; Oligonucleotides, Antisense; Phenotype
PubMed: 32486152
DOI: 10.3390/ijms21113903 -
Duchenne muscular dystrophy: Current treatment and emerging exon skipping and gene therapy approach.European Journal of Pharmacology May 2023Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that causes debilitating muscle weakness and atrophy due to a loss of the dystrophin... (Review)
Review
Duchenne muscular dystrophy (DMD) is an X-linked recessive neuromuscular disorder that causes debilitating muscle weakness and atrophy due to a loss of the dystrophin protein. Patients with DMD are commonly diagnosed at about 3-5 years of age and progressively decline until complications of the disease often result in death at about 20 years of age. While there is no current cure for DMD, several treatment options focus on improving the quality of life and slowing progression of symptoms associated with the disease. The current treatment for DMD is glucocorticoids and physical therapy. Respiratory therapy, cardiac management, bone health maintenance, orthopedic interventions, and dietary considerations are also utilized in managing DMD patients. Emerging therapeutic approaches include gene transfer therapy using adeno-associated virus (AAV) vectors, and exon skipping agents. Both approaches have been shown to be relatively safe, with few significant side effects. Even though exon skipping agents produce a smaller dystrophin protein, they effectively preserve a significant portion of its function. Exon skipping agents have clinical advantages over traditional therapies, such as corticosteroids, because they slow the progression of DMD in addition to relieving symptoms. This review discusses the pathogenesis of DMD and explores the current treatment options as well as new and emerging therapies.
Topics: Humans; Muscular Dystrophy, Duchenne; Dystrophin; Quality of Life; Oligonucleotides, Antisense; Genetic Therapy; Exons
PubMed: 36963652
DOI: 10.1016/j.ejphar.2023.175675 -
Journal of the American College of... Nov 2021Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular... (Review)
Review
Detecting familial hypercholesterolemia (FH) early and "normalizing" low-density lipoprotein (LDL) cholesterol values are the 2 pillars for effective cardiovascular disease prevention in FH. Combining lipid-lowering therapies targeting synergistic/complementary metabolic pathways makes this feasible, even among severe phenotypes. For LDL receptor-dependent treatments, PCSK9 remains the main target for adjunctive therapy to statins and ezetimibe through a variety of approaches. These include protein inhibition (adnectins), inhibition of translation at mRNA level (antisense oligonucleotides or small interfering RNA), and creation of loss-of-function mutations through base-pair editing. For patients with little LDL receptor function, LDL receptor-independent treatment targeting ANGPTL3 through monoclonal therapies are now available, or in the future, antisense/small interfering RNA-based approaches offer alternative approaches. Finally, first-in-human studies are ongoing, testing adenovirus-mediated gene therapy transducing healthy LDLR DNA in patients with HoFH. Further development of the CRISPR cas technology, which has shown promising results in vivo on introducing PCSK9 loss-of-function mutations, will move a single-dose, curative treatment for FH closer.
Topics: Cardiovascular Diseases; Cholesterol, LDL; Drug Development; Early Diagnosis; Humans; Hyperlipoproteinemia Type II; Lipid Regulating Agents; Therapies, Investigational
PubMed: 34711342
DOI: 10.1016/j.jacc.2021.09.004 -
RNA Biology 2022RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug... (Review)
Review
RNA-based therapeutics have entered the mainstream with seemingly limitless possibilities to treat all categories of neurological disease. Here, common RNA-based drug modalities such as antisense oligonucleotides, small interfering RNAs, RNA aptamers, RNA-based vaccines and mRNA drugs are reviewed highlighting their current and potential applications. Rapid progress has been made across rare genetic diseases and neurodegenerative disorders, but safe and effective delivery to the brain remains a significant challenge for many applications. The advent of individualized RNA-based therapies for ultra-rare diseases is discussed against the backdrop of the emergence of this field into more common conditions such as Alzheimer's disease and ischaemic stroke. There remains significant untapped potential in the use of RNA-based therapeutics for behavioural disorders and tumours of the central nervous system; coupled with the accelerated development expected over the next decade, the true potential of RNA-based therapeutics to transform the therapeutic landscape in neurology remains to be uncovered.
Topics: Animals; Aptamers, Nucleotide; Disease Management; Disease Susceptibility; Gene Expression Regulation; Genetic Therapy; Humans; Nervous System Diseases; RNA; RNA Interference; RNA, Small Interfering; RNAi Therapeutics; Targeted Gene Repair
PubMed: 35067193
DOI: 10.1080/15476286.2021.2021650