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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 -
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 -
Neurology. Genetics Apr 2019There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal... (Review)
Review
There are few disease-modifying therapeutics for neurodegenerative diseases, but successes on the development of antisense oligonucleotide (ASO) therapeutics for spinal muscular atrophy and Duchenne muscular dystrophy predict a robust future for ASOs in medicine. Indeed, existing pipelines for the development of ASO therapies for spinocerebellar ataxias, Huntington disease, Alzheimer disease, amyotrophic lateral sclerosis, Parkinson disease, and others, and increased focus by the pharmaceutical industry on ASO development, strengthen the outlook for using ASOs for neurodegenerative diseases. Perhaps the most significant advantage to ASO therapeutics over other small molecule approaches is that acquisition of the target sequence provides immediate knowledge of putative complementary oligonucleotide therapeutics. In this review, we describe the various types of ASOs, how they are used therapeutically, and the present efforts to develop new ASO therapies that will contribute to a forthcoming toolkit for treating multiple neurodegenerative diseases.
PubMed: 31119194
DOI: 10.1212/NXG.0000000000000323 -
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 -
Cell Host & Microbe Jul 2019The global challenges presented by drug-resistant bacterial infections have stimulated much activity in finding new treatments. This review summarizes the progress and... (Review)
Review
The global challenges presented by drug-resistant bacterial infections have stimulated much activity in finding new treatments. This review summarizes the progress and setbacks of non-traditional approaches intent on circumventing bacterial drug resistance. These approaches include targeting virulence via toxin production and virulence factor secretion, impeding bacterial adhesion to host cells and biofilm formation, interrupting or inhibiting bacterial communication, and downregulating virulence. Other strategies include immune evasion, microbiome-modifying therapies, and the employment of phages as treatments or carriers. Finally, the prospects of nanoparticles, immunotherapy, antisense RNA, and drug-resistance-modulation approaches are discussed. The development of non-traditional treatments suffers similar challenges faced by developers of conventional antibiotics; however, most of these new strategies have additional and considerable hurdles before it can be shown that they are safe and efficacious for patient use. For the foreseeable future, it is likely that most of these treatments, if approved, will be used in combination with antibiotics.
Topics: Bacterial Infections; Biological Therapy; Drug Therapy; Humans
PubMed: 31295426
DOI: 10.1016/j.chom.2019.06.004 -
Cold Spring Harbor Perspectives in... Sep 2010Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene... (Review)
Review
Inactivation of p53 functions is an almost universal feature of human cancer cells. This has spurred a tremendous effort to develop p53 based cancer therapies. Gene therapy using wild-type p53, delivered by adenovirus vectors, is now in widespread use in China. Other biologic approaches include the development of oncolytic viruses designed to replicate and kill only p53 defective cells and also the development of siRNA and antisense RNA's that activate p53 by inhibiting the function of the negative regulators Mdm2, MdmX, and HPV E6. The altered processing of p53 that occurs in tumor cells can elicit T-cell and B-cell responses to p53 that could be effective in eliminating cancer cells and p53 based vaccines are now in clinical trial. A number of small molecules that directly or indirectly activate the p53 response have also reached the clinic, of which the most advanced are the p53 mdm2 interaction inhibitors. Increased understanding of the p53 response is also allowing the development of powerful drug combinations that may increase the selectivity and safety of chemotherapy, by selective protection of normal cells and tissues.
Topics: Animals; Cancer Vaccines; Genetic Therapy; Humans; Molecular Targeted Therapy; Neoplasms; Proto-Oncogene Proteins c-mdm2; RNA, Small Interfering; Tumor Suppressor Protein p53
PubMed: 20463003
DOI: 10.1101/cshperspect.a001222 -
ELife Jan 2023encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the antisense transcript (). This leaves neurons...
encodes ubiquitin protein ligase E3A, and in neurons its expression from the paternal allele is repressed by the antisense transcript (). This leaves neurons susceptible to loss-of-function of maternal . Indeed, Angelman syndrome, a severe neurodevelopmental disorder, is caused by maternal deficiency. A promising therapeutic approach to treating Angelman syndrome is to reactivate the intact paternal by suppressing . Prior studies show that many neurological phenotypes of maternal knockout mice can only be rescued by reinstating expression in early development, indicating a restricted therapeutic window for Angelman syndrome. Here, we report that reducing by antisense oligonucleotides in juvenile or adult maternal knockout mice rescues the abnormal electroencephalogram (EEG) rhythms and sleep disturbance, two prominent clinical features of Angelman syndrome. Importantly, the degree of phenotypic improvement correlates with the increase of Ube3a protein levels. These results indicate that the therapeutic window of genetic therapies for Angelman syndrome is broader than previously thought, and EEG power spectrum and sleep architecture should be used to evaluate the clinical efficacy of therapies.
Topics: Mice; Animals; Angelman Syndrome; Brain; Oligonucleotides, Antisense; Mice, Knockout; Sleep; Ubiquitin-Protein Ligases; Disease Models, Animal
PubMed: 36594817
DOI: 10.7554/eLife.81892 -
Neurotherapeutics : the Journal of the... Apr 2015Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to cell death of predominantly motor neurons. Despite extensive research in this disease,... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease leading to cell death of predominantly motor neurons. Despite extensive research in this disease, finding a way to slow the progress of the disease has been challenging. RNA-targeted therapeutic approaches, including small interfering RNA and antisense oligonucleotides are being developed for genetic forms of ALS. ALS provides an unique opportunity for the use of RNA inhibition strategies given a well-defined animal model, extensive available information regarding the causative genes, and recent experience in phase 1 clinical trial.
Topics: Amyotrophic Lateral Sclerosis; Animals; Genetic Therapy; Humans; RNA; RNA, Small Interfering
PubMed: 25753730
DOI: 10.1007/s13311-015-0344-z -
Molecular Therapy : the Journal of the... May 2017Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and... (Review)
Review
Oligonucleotides (oligos) have been under clinical development for approximately the past 30 years, beginning with antisense oligonucleotides (ASOs) and apatmers and followed about 15 years ago by siRNAs. During that lengthy period of time, numerous clinical trials have been performed and thousands of trial participants accrued onto studies. Of all the molecules evaluated as of January 2017, the regulatory authorities assessed that six provided clear clinical benefit in rigorously controlled trials. The story of these six is given in this review.
Topics: Aptamers, Nucleotide; Clinical Trials as Topic; Cytomegalovirus Retinitis; Drug Approval; Hepatic Veno-Occlusive Disease; Humans; Hypercholesterolemia; Macular Degeneration; Morpholinos; Muscular Atrophy, Spinal; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Polydeoxyribonucleotides; Thionucleotides
PubMed: 28366767
DOI: 10.1016/j.ymthe.2017.03.023 -
Cold Spring Harbor Perspectives in... Mar 2017The excitement around the entry into the clinic of the first generation of p53-specific drugs has become muted as the hoped-for dramatic clinical responses have not yet... (Review)
Review
The excitement around the entry into the clinic of the first generation of p53-specific drugs has become muted as the hoped-for dramatic clinical responses have not yet been seen. However, these pioneer molecules have become exceptionally powerful tools in the analysis of the p53 pathway and, as a result, a whole spectrum of new interventions are being explored. These include entirely novel and innovative approaches to drug discovery, such as the use of exon-skipping antisense oligonucleotides and T-cell-receptor-based molecules. The extraordinary resources available to the p53 community in terms of reagents, models, and collaborative networks are generating breakthrough approaches to medicines for oncology and also for other diseases in which aberrant p53 signaling plays a role.
Topics: Animals; Disease Models, Animal; Drug Discovery; Gene Expression Profiling; Genetic Therapy; Humans; Mice; Molecular Targeted Therapy; Mutation; Neoplasms; Oligonucleotides, Antisense; Receptors, Antigen, T-Cell; Tumor Suppressor Protein p53
PubMed: 28193768
DOI: 10.1101/cshperspect.a026310