-
The International Journal of... May 2019Amyotrophic lateral sclerosis (ALS) is a disease with highly heterogenous causes, most of which remain unknown, a multitude of possible disease mechanisms, and no... (Review)
Review
Amyotrophic lateral sclerosis (ALS) is a disease with highly heterogenous causes, most of which remain unknown, a multitude of possible disease mechanisms, and no therapy currently available that can halt disease progression. However, recent advances in antisense oligonucleotides have made them a viable option for targeted therapeutics for patients. These molecules offer a method of targeting RNA that is highly specific, adaptable, and does not require viral delivery. Antisense oligonucleotides are therefore being developed for several genetic causes of ALS. Furthermore, biological pathways involved in the pathogenesis of disease also offer tantalizing targets for intervention using antisense oligonucleotides. Here we detail existing and potential targets for antisense oligonucleotides in ALS and briefly examine the requirements for these drugs to reach and be effective in clinic.
Topics: Amyotrophic Lateral Sclerosis; Drug Delivery Systems; Humans; Molecular Targeted Therapy; Oligonucleotides, Antisense
PubMed: 30904737
DOI: 10.1016/j.biocel.2019.03.009 -
European Journal of Immunology Nov 2023Transforming growth factor (TGF)-β1, a member of the TGF-β superfamily, is produced by many immune and nonimmune cells and has pleiotropic effects on both innate and... (Review)
Review
Transforming growth factor (TGF)-β1, a member of the TGF-β superfamily, is produced by many immune and nonimmune cells and has pleiotropic effects on both innate and adaptive immunity, especially in the control of T-cell differentiation and function. Consistently, loss of TGF-β1 function is associated with exacerbated T-cell-dependent inflammatory responses that culminate in pathological processes in allergic and immune-mediated diseases. In this review, we highlight the roles of TGF-β1 in immunity, focusing mainly on its ability to promote differentiation of regulatory T cells, T helper (Th)-17, and Th9 cells, thus contributing to amplifying or restricting T-cell responses in health and human diseases (e.g., inflammatory bowel diseases, type 1 diabetes, asthma, and MS). In addition, we discuss the involvement of Smad7, an inhibitor of TGF-β1 signaling, in immune-mediated disorders (e.g., psoriasis, rheumatoid arthritis, MS, and inflammatory bowel diseases), as well as the discordant results of clinical trials with mongersen, an oral pharmaceutical compound containing a Smad7 antisense oligonucleotide, in patients with Crohn's disease. Further work is needed to ascertain the reasons for such a discrepancy as well as to identify better candidates for treatment with Smad7 inhibitors.
Topics: Humans; Crohn Disease; Inflammatory Bowel Diseases; Oligonucleotides, Antisense; Smad7 Protein; Transforming Growth Factor beta; Transforming Growth Factor beta1
PubMed: 37611637
DOI: 10.1002/eji.202350460 -
Nature Reviews. Drug Discovery Jun 2023
Topics: Humans; Oligonucleotides, Antisense; Glioma; Brain Neoplasms; Oligonucleotides
PubMed: 37165091
DOI: 10.1038/d41573-023-00077-x -
Wiley Interdisciplinary Reviews. RNA Jul 2022The COVID-19 crisis and the development of the first approved mRNA vaccine have highlighted the power of RNA-based therapeutic strategies for the development of new... (Review)
Review
The COVID-19 crisis and the development of the first approved mRNA vaccine have highlighted the power of RNA-based therapeutic strategies for the development of new medicines. Aside from RNA-vaccines, antisense oligonucleotides (ASOs) represent a new and very promising class of RNA-targeted therapy. Few drugs have already received approval from the Food and Drug Administration. Here, we underscored why and how ASOs hold the potential to change the therapeutic landscape to beat SARS-CoV-2 viral infections. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Small Molecule-RNA Interactions.
Topics: Humans; Oligonucleotides; Oligonucleotides, Antisense; RNA; SARS-CoV-2; United States; Vaccines, Synthetic; mRNA Vaccines; COVID-19 Drug Treatment
PubMed: 34842345
DOI: 10.1002/wrna.1703 -
Cells Jan 2020The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based... (Review)
Review
The first therapeutic nucleic acid, a DNA oligonucleotide, was approved for clinical use in 1998. Twenty years later, in 2018, the first therapeutic RNA-based oligonucleotide was United States Food and Drug Administration (FDA) approved. This promises to be a rapidly expanding market, as many emerging biopharmaceutical companies are developing RNA interference (RNAi)-based, and RNA-based antisense oligonucleotide therapies. However, miRNA therapeutics are noticeably absent. miRNAs are regulatory RNAs that regulate gene expression. In disease states, the expression of many miRNAs is measurably altered. The potential of miRNAs as therapies and therapeutic targets has long been discussed and in the context of a wide variety of infections and diseases. Despite the great number of studies identifying miRNAs as potential therapeutic targets, only a handful of miRNA-targeting drugs (mimics or inhibitors) have entered clinical trials. In this review, we will discuss whether the investment in finding potential miRNA therapeutic targets has yielded feasible and practicable results, the benefits and obstacles of miRNAs as therapeutic targets, and the potential future of the field.
Topics: Alternative Splicing; Animals; Gene Transfer Techniques; Humans; MicroRNAs; Models, Biological; Oligonucleotides, Antisense
PubMed: 31936122
DOI: 10.3390/cells9010137 -
EMBO Molecular Medicine May 2023Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of...
Neurodegenerative diseases are increasingly prevalent in the aging population, yet no disease-modifying treatments are currently available. Increasing the expression of the cold-shock protein RBM3 through therapeutic hypothermia is remarkably neuroprotective. However, systemic cooling poses a health risk, strongly limiting its clinical application. Selective upregulation of RBM3 at normothermia thus holds immense therapeutic potential. Here we identify a poison exon within the RBM3 gene that is solely responsible for its cold-induced expression. Genetic removal or antisense oligonucleotide (ASO)-mediated manipulation of this exon yields high RBM3 levels independent of cooling. Notably, a single administration of ASO to exclude the poison exon, using FDA-approved chemistry, results in long-lasting increased RBM3 expression in mouse brains. In prion-diseased mice, this treatment leads to remarkable neuroprotection, with prevention of neuronal loss and spongiosis despite high levels of disease-associated prion protein. Our promising results in mice support the possibility that RBM3-inducing ASOs might also deliver neuroprotection in humans in conditions ranging from acute brain injury to Alzheimer's disease.
Topics: Humans; Mice; Animals; Aged; Temperature; Oligonucleotides, Antisense; Poisons; RNA-Binding Proteins; Cold Temperature
PubMed: 36946385
DOI: 10.15252/emmm.202217157 -
Nucleic Acids Research Feb 2018RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and... (Review)
Review
RNA plays a central role in the expression of all genes. Because any sequence within RNA can be recognized by complementary base pairing, synthetic oligonucleotides and oligonucleotide mimics offer a general strategy for controlling processes that affect disease. The two primary antisense approaches for regulating expression through recognition of cellular RNAs are single-stranded antisense oligonucleotides and duplex RNAs. This review will discuss the chemical modifications and molecular mechanisms that make synthetic nucleic acid drugs possible. Lessons learned from recent clinical trials will be summarized. Ongoing clinical trials are likely to decisively test the adequacy of our current generation of antisense nucleic acid technologies and highlight areas where more basic research is needed.
Topics: Alternative Splicing; Clinical Trials as Topic; Humans; MicroRNAs; Oligonucleotides, Antisense; Protein Biosynthesis; Proteins; RNA Interference; RNA, Double-Stranded
PubMed: 29240946
DOI: 10.1093/nar/gkx1239 -
Progress in Molecular Biology and... 2024RNA therapy is one of the new treatments using small RNA molecules to target and regulate gene expression. It involves the application of synthetic or modified RNA...
RNA therapy is one of the new treatments using small RNA molecules to target and regulate gene expression. It involves the application of synthetic or modified RNA molecules to inhibit the expression of disease-causing genes specifically. In other words, it silences genes and suppresses the transcription process. The main theory behind RNA therapy is that RNA molecules can prevent the translation into proteins by binding to specific messenger RNA (mRNA) molecules. By targeting disease-related mRNA molecules, RNA therapy can effectively silence or reduce the development of harmful proteins. There are different types of RNA molecules used in therapy, including small interfering RNAs (siRNAs), microRNAs (miRNAs), aptamer, ribozyme, and antisense oligonucleotides (ASOs). These molecules are designed to complement specific mRNA sequences, allowing them to bind and degrade the targeted mRNA or prevent its translation into protein. Nanotechnology is also highlighted to increase the efficacy of RNA-based drugs. In this chapter, while examining various methods of RNA therapy, we discuss the advantages and challenges of each.
Topics: Humans; MicroRNAs; RNA, Small Interfering; Oligonucleotides; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 38360005
DOI: 10.1016/bs.pmbts.2023.12.022 -
Scientific Reports Feb 2023Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic...
Previous study from our lab has revealed a new role of CD47 in regulating adipose tissue function, energy homeostasis and the development of obesity and metabolic disease in CD47 deficient mice. In this study, the therapeutic potential of an antisense oligonucleotide (ASO) targeting to CD47 in obesity and its-associated complications was determined in two obese mouse models (diet induced and genetic models). In diet induced obesity, male C57BL6 mice were fed with high fat (HF) diet to induce obesity and then treated with CD47ASO or control ASO for 8 weeks. In genetic obese mouse model, male six-week old ob/ob mice were treated with ASOs for 9 weeks. We found that CD47ASO treatment reduced HF diet-induced weight gain, decreased fat mass, prevented dyslipidemia, and improved glucose tolerance. These changes were accompanied by reduced inflammation in white adipose tissue and decreased hepatic steatosis. This protection was also seen in CD47ASO treated ob/ob mice. Mechanistically, CD47ASO treatment increased mice physical activity and energy expenditure, contributing to weight loss and improved metabolic outcomes in obese mice. Collectively, these findings suggest that CD47ASO might serve as a new treatment option for obesity and its-associated metabolic complications.
Topics: Animals; Male; Mice; CD47 Antigen; Diet, High-Fat; Insulin Resistance; Liver; Mice, Inbred C57BL; Mice, Obese; Obesity; Oligonucleotides, Antisense
PubMed: 36797364
DOI: 10.1038/s41598-023-30006-2 -
Current Opinion in Lipidology Jun 2022Lipoprotein(a) (Lp[a]) is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization.... (Review)
Review
PURPOSE OF REVIEW
Lipoprotein(a) (Lp[a]) is a likely causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and aortic valve disease, confirmed by Mendelian randomization. With reliable assays, it has been established that Lp(a) is linearly associated with ASCVD. Current low-density lipoprotein cholesterol (LDL-C) lowering therapies do not or minimally lower Lp(a). This review focuses on the clinical importance and therapeutic consequences of Lp(a) measurement.
RECENT FINDINGS
Development of RNA-based Lp(a) lowering therapeutics has positioned Lp(a) as one of the principal residual risk factors to target in the battle against lipid-driven ASCVD risk. Pelacarsen, which is a liver-specific antisense oligonucleotide, has shown Lp(a) reductions up to 90% and its phase 3 trial is currently underway. Olpasiran is a small interfering RNA targeting LPA messenger RNA which is being investigated in phase 2 and has already shown dose-dependent Lp(a) reductions up to 90%.
SUMMARY
Lp(a) should be measured in every patient at least once to identify patients with very high Lp(a) levels. These patients could benefit from Lp(a) lowering therapies when approved. In the meantime, therapy in high Lp(a) patients should focus on further reducing LDL-C and other ASCVD risk factors.
Topics: Atherosclerosis; Cardiovascular Diseases; Cholesterol, LDL; Humans; Lipoprotein(a); Oligonucleotides, Antisense; Risk Factors
PubMed: 35695619
DOI: 10.1097/MOL.0000000000000828