-
Current Medicinal Chemistry 2022Retinal degenerative diseases are the main retinal diseases that threaten vision. Most retinal degenerative diseases are inherited diseases, including autosomal... (Review)
Review
Retinal degenerative diseases are the main retinal diseases that threaten vision. Most retinal degenerative diseases are inherited diseases, including autosomal recessive inheritance, autosomal dominant inheritance, X-linked inheritance, and mitochondrial inheritance; therefore, emerging gene therapy strategies may provide an alternative method of treatment. Currently, three viral vectors are usually used in gene therapy studies: adenovirus, lentivirus, and adeno-associated virus. Other gene therapies have their own advantages, such as DNA nanoparticles, antisense oligonucleotides, and gene editing therapies. In addition, retinal degenerative diseases are often accompanied by abnormalities of retinal cells, including photoreceptor and retinal pigment epithelial cells. At present, stem cell transplantation is a promising new treatment for retinal degenerative diseases. Common sources of stem cells include retinal progenitor cells, induced pluripotent stem cells, embryonic stem cells, and mesenchymal stem cells. In addition, retina explant cultures in vitro can be used as an effective platform for screening new therapies for retinal degenerative diseases. Drugs that actually reach the retinal layer are more controlled, more consistent, and less invasive when using retinal explants. Furthermore, studies have shown that the imbalance of the gut microbiota is closely related to the occurrence and development of diabetic retinopathy. Therefore, the progression of diabetic retinopathy may be restrained by adjusting the imbalance of the gut microbiota. The purpose of this review is to discuss and summarize the molecular mechanisms and potential therapeutic strategies of retinal degenerative diseases.
Topics: Diabetic Retinopathy; Humans; Induced Pluripotent Stem Cells; Oligonucleotides, Antisense; Retina; Retinal Degeneration; Retinal Pigment Epithelium; Retinal Pigments; Stem Cell Transplantation
PubMed: 34844533
DOI: 10.2174/0929867328666211129122908 -
Nucleic Acid Therapeutics Feb 2018Nucleic acid therapeutics are an established class of drugs that enable specific targeting of a gene of interest. This diverse family of drugs includes antisense... (Review)
Review
Nucleic acid therapeutics are an established class of drugs that enable specific targeting of a gene of interest. This diverse family of drugs includes antisense oligonucleotides, siRNAs, and mRNA replacement therapies, which can elicit both gene repression and activation, primarily at the RNA level. Recent advances in medicinal chemistry have increased drug potency and enhanced delivery and distribution to a broad array of tissue and cell types. A key advantage of nucleic acid therapeutics is in their application to monogenic diseases. Cystic fibrosis (CF) is one such disease that affects ∼70,000 people globally. This severe disease is an excellent candidate for nucleic acid therapies, as it is due to a genetic defect in a single epithelial chloride channel. Although CF affects many tissues, the primary cause of patient mortality is lung disease. Here we review the various nucleic acid therapeutic modalities and their mechanisms of action, the opportunities and challenges associated with application of nucleic acid drugs to the lung pathology of CF, and the current state and prospects for nucleic acid drugs for the treatment of CF.
Topics: Administration, Inhalation; Animals; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Epithelial Sodium Channels; Gene Transfer Techniques; Genetic Therapy; Humans; Loss of Function Mutation; Lung; Mice; Oligonucleotides, Antisense; RNA Splicing; RNA, Messenger; RNA, Small Interfering; Ribonuclease H
PubMed: 29160746
DOI: 10.1089/nat.2017.0696 -
Advances in Experimental Medicine and... 2019In recent years, the RNA molecule became one of the most promising targets for therapeutic intervention. Currently, a large number of RNA-based therapeutics are being... (Review)
Review
In recent years, the RNA molecule became one of the most promising targets for therapeutic intervention. Currently, a large number of RNA-based therapeutics are being investigated both at the basic research level and in late-stage clinical trials. Some of them are even already approved for treatment. RNA-based approaches can act at pre-mRNA level (by splicing modulation/correction using antisense oligonucleotides or U1snRNA vectors), at mRNA level (inhibiting gene expression by siRNAs and antisense oligonucleotides) or at DNA level (by editing mutated sequences through the use of CRISPR/Cas). Other RNA approaches include the delivery of in vitro transcribed (IVT) mRNA or the use of oligonucleotides aptamers. Here we review these approaches and their translation into clinics trying to give a brief overview also on the difficulties to its application as well as the research that is being done to overcome them.
Topics: Genetic Therapy; Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA Splicing; RNA, Messenger; RNA, Small Interfering
PubMed: 31342441
DOI: 10.1007/978-3-030-19966-1_7 -
International Journal of Biological... Nov 2022Non-healing wounds have long been the subject of scientific and clinical investigations. Despite breakthroughs in understanding the biology of delayed wound healing,... (Review)
Review
Non-healing wounds have long been the subject of scientific and clinical investigations. Despite breakthroughs in understanding the biology of delayed wound healing, only limited advances have been made in properly treating wounds. Recently, research into nucleic acids (NAs) such as small-interfering RNA (siRNA), microRNA (miRNA), plasmid DNA (pDNA), aptamers, and antisense oligonucleotides (ASOs) has resulted in the development of a latest therapeutic strategy for wound healing. In this regard, dendrimers, scaffolds, lipid nanoparticles, polymeric nanoparticles, hydrogels, and metal nanoparticles have all been explored as NA delivery techniques. However, the translational possibility of NA remains a substantial barrier. As a result, different NAs must be identified, and their distribution method must be optimized. This review explores the role of NA-based therapeutics in various stages of wound healing and provides an update on the most recent findings in the development of NA-based nanomedicine and biomaterials, which may offer the potential for the invention of novel therapies for this long-term condition. Further, the challenges and potential for miRNA-based techniques to be translated into clinical applications are also highlighted.
Topics: Biocompatible Materials; DNA; Dendrimers; Hydrogels; Liposomes; MicroRNAs; Nanoparticles; Nucleic Acids; Oligonucleotides, Antisense; RNA, Small Interfering; Wound Healing
PubMed: 35987365
DOI: 10.1016/j.ijbiomac.2022.08.099 -
Journal of Human Genetics Sep 2021MicroRNA (miRNA; miR) is a functionally small non-coding RNA and can negatively regulate gene expression by directly binding to the target gene. Some miRNAs are closely... (Review)
Review
MicroRNA (miRNA; miR) is a functionally small non-coding RNA and can negatively regulate gene expression by directly binding to the target gene. Some miRNAs are closely involved in the development and progression of cancer and are abnormally expressed in many cancer types. Therefore, control of the expression of cancer-associated miRNAs is expected as a next-generation drug modality to treat advanced types of cancers with high unmet medical needs. Indeed, miRNA therapeutics, which are based on the functional inhibition of oncogenic miRNA (OncomiR) using antisense oligonucleotides (anti-miR) and the replacement via the introduction of a synthetic miRNA mimic for tumor suppressive miRNA (TS-miR), have been developed. In this review, we summarize cancer-associated miRNAs related to various cancer pathologies and their clinical application to miRNA therapeutics for cancer.
Topics: Gene Expression Regulation, Neoplastic; Humans; MicroRNAs; Molecular Targeted Therapy; Neoplasms
PubMed: 34088973
DOI: 10.1038/s10038-021-00938-6 -
Journal of Controlled Release :... Jan 2016A myriad of pathologies affect the gastrointestinal tract, citing this affected area as a significant target for therapeutic intervention. One group of therapeutic... (Review)
Review
A myriad of pathologies affect the gastrointestinal tract, citing this affected area as a significant target for therapeutic intervention. One group of therapeutic agents, antisense and oligonucleotides and small interfering RNAs, offer a promising platform for treating a wide variety of diseases ranging from cancer to auto-immune diseases. Current delivery methods are carried out either systemically or locally into diseased areas, both of which involve needles. The challenge in orally administering this type of treatment lies in the complications that arise due to the vast environmental extremes found within the gastrointestinal tract, owing to the fact that, as the drug travels down the gastrointestinal tract, it is subjected to pH changes and interactions with bacteria and a variety of digestive and protective enzymes including proteases, DNAses, and RNAses. Overcoming these challenges to allow the practical application of these drugs is a priority that has invoked a multitude of research in the chemical, biological, and material sciences. In this review, we will address common gastrointestinal pathologies, the barriers to oral-based therapies and antisense-interfering technologies, the approaches that have already been applied for their delivery, and the current status of antisense drug therapy clinical trials for gastrointestinal-related disorders.
Topics: Animals; Drug Delivery Systems; Gastrointestinal Diseases; Gastrointestinal Tract; Gene Transfer Techniques; Humans; Needles; Oligonucleotides, Antisense; RNA, Small Interfering
PubMed: 26646543
DOI: 10.1016/j.jconrel.2015.11.031 -
Expert Opinion on Emerging Drugs Sep 2021Huntington's disease is a neurodegenerative disease that is characterized by motor dysfunction, behavioral/psychiatric symptoms, and cognitive impairment. Because of the... (Review)
Review
INTRODUCTION
Huntington's disease is a neurodegenerative disease that is characterized by motor dysfunction, behavioral/psychiatric symptoms, and cognitive impairment. Because of the lack of availability of curative or disease modifying treatments, much of clinical practice in HD care to date has focused on symptomatic treatment. Recent work has created optimism surrounding possible emerging disease modifying therapeutics. HD is a developing therapeutic field with diverse and promising emerging therapies.
AREAS COVERED
A PubMed literature review was completed to discover pertinent reviews and analyses. ClinicalTrials.gov was referenced to find updated information about ongoing and planned trials. Lastly, because of the rapidly evolving nature of HD treatments, drug manufacturer websites and press releases were reviewed to provide current information surrounding recently reported trial results.
EXPERT OPINION
Recent setbacks involving antisense oligonucleotide research should not diminish enthusiasm and hope for the many other novel therapies currently being pursued. We remain optimistic about the many promising emerging therapies for HD, and we expect that growing knowledge about the pathophysiology of the underlying disease and constant advances in biotechnology will lead to therapies that have a meaningful impact in the lives of patients, their families, and those who care for them.
Topics: Humans; Huntington Disease; Neurodegenerative Diseases; Oligonucleotides, Antisense
PubMed: 34319843
DOI: 10.1080/14728214.2021.1962285 -
Current Opinion in Cardiology May 2020Cardiovascular disease is the leading cause of death globally, with the number of deaths rising every year. Much effort has gone into development of new treatment... (Review)
Review
PURPOSE OF REVIEW
Cardiovascular disease is the leading cause of death globally, with the number of deaths rising every year. Much effort has gone into development of new treatment strategies. Many RNA species have important regulatory functions in disease initiation and progression, providing interesting new treatment options. This review focuses on different classes of RNA-based therapeutics and provides examples of current clinical and preclinical studies. Current challenges that prevent clinical translation and possibilities to overcome them will be discussed.
RECENT FINDINGS
Different RNA-based molecules have been developed, such as antisense oligos, microRNA mimics and small interfering RNAs. Modifications are used to prevent degradation and immune activation and improve affinity. Additionally, in order to improve delivery of the RNA molecules to the target tissues, viral or nonviral vectors can be used.
SUMMARY
RNA-based therapy has been shown to be a promising new treatment strategy for different disorders. However, several challenges, such as delivery problems and low efficacy remain. Future research will likely focus on effective delivery to target tissues in order to improve efficacy and avoid harmful side-effects.
Topics: Cardiovascular Diseases; Drug Delivery Systems; Genetic Therapy; Humans; MicroRNAs; RNA, Small Interfering
PubMed: 32068614
DOI: 10.1097/HCO.0000000000000724 -
Genes Jan 2022Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of... (Review)
Review
Duchenne muscular dystrophy (DMD) is a fatal genetic disease affecting children that is caused by a mutation in the gene encoding for dystrophin. In the absence of functional dystrophin, patients experience progressive muscle deterioration, leaving them wheelchair-bound by age 12 and with few patients surviving beyond their third decade of life as the disease advances and causes cardiac and respiratory difficulties. In recent years, an increasing number of antisense and gene therapies have been studied for the treatment of muscular dystrophy; however, few of these therapies focus on treating mutations arising in the N-terminal encoding region of the dystrophin gene. This review summarizes the current state of development of N-terminal antisense and gene therapies for DMD, mainly focusing on exon-skipping therapy for duplications and deletions, as well as microdystrophin therapy.
Topics: Child; Dystrophin; Exons; Genetic Therapy; Humans; Muscular Dystrophy, Duchenne; Mutation
PubMed: 35205302
DOI: 10.3390/genes13020257 -
Cancer Metastasis Reviews Sep 2017Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer... (Review)
Review
Over 90% of head and neck cancers overexpress the epidermal growth factor receptor (EGFR). In diverse tumor types, EGFR overexpression has been associated with poorer prognosis and outcomes. Therapies targeting EGFR include monoclonal antibodies, tyrosine kinase inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and antisense gene therapy. Few EGFR-targeted therapeutics are approved for clinical use. The monoclonal antibody cetuximab is a Food and Drug Administration (FDA)-approved EGFR-targeted therapy, yet has exhibited modest benefit in clinical trials. The humanized monoclonal antibody nimotuzumab is also approved for head and neck cancers in Cuba, Argentina, Colombia, Peru, India, Ukraine, Ivory Coast, and Gabon in addition to nasopharyngeal cancers in China. Few other EGFR-targeted therapeutics for head and neck cancers have led to as significant responses as seen in lung carcinomas, for instance. Recent genome sequencing of head and neck tumors has helped identify patient subgroups with improved response to EGFR inhibitors, for example, cetuximab in patients with the KRAS-variant and the tyrosine kinase inhibitor erlotinib for tumors harboring MAPK1 mutations. Genome sequencing has furthermore broadened our understanding of dysregulated pathways, holding the potential to enhance the benefit derived from therapies targeting EGFR.
Topics: Animals; Carcinoma, Squamous Cell; ErbB Receptors; Genetic Therapy; Head and Neck Neoplasms; Humans; Molecular Targeted Therapy; Protein Kinase Inhibitors; Randomized Controlled Trials as Topic; Squamous Cell Carcinoma of Head and Neck
PubMed: 28866730
DOI: 10.1007/s10555-017-9687-8