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Nucleic Acids Research Jan 2021Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that...
Antisense oligonucleotides (ASOs) have emerged as a new class of drugs to treat a wide range of diseases, including neurological indications. Spinraza, an ASO that modulates splicing of SMN2 RNA, has shown profound disease modifying effects in Spinal Muscular Atrophy (SMA) patients, energizing efforts to develop ASOs for other neurological diseases. While SMA specifically affects spinal motor neurons, other neurological diseases affect different central nervous system (CNS) regions, neuronal and non-neuronal cells. Therefore, it is important to characterize ASO distribution and activity in all major CNS structures and cell types to have a better understanding of which neurological diseases are amenable to ASO therapy. Here we present for the first time the atlas of ASO distribution and activity in the CNS of mice, rats, and non-human primates (NHP), species commonly used in preclinical therapeutic development. Following central administration of an ASO to rodents, we observe widespread distribution and target RNA reduction throughout the CNS in neurons, oligodendrocytes, astrocytes and microglia. This is also the case in NHP, despite a larger CNS volume and more complex neuroarchitecture. Our results demonstrate that ASO drugs are well suited for treating a wide range of neurological diseases for which no effective treatments are available.
Topics: Animals; Central Nervous System; Female; In Situ Hybridization; Injections, Intraventricular; Injections, Spinal; Macaca fascicularis; Male; Mice; Neuroglia; Neurons; Oligonucleotides, Antisense; Organ Specificity; Primates; RNA, Long Noncoding; Rats; Rats, Sprague-Dawley; Ribonuclease H; Tissue Distribution
PubMed: 33367834
DOI: 10.1093/nar/gkaa1235 -
Cancer Immunology Research Apr 2023Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the...
Diverse factors contribute to the limited clinical response to radiotherapy (RT) and immunotherapy in metastatic non-small cell lung cancer (NSCLC), among which is the ability of these tumors to recruit a retinue of suppressive immune cells-such as M2 tumor-associated macrophages (TAM)-thereby establishing an immunosuppressive tumor microenvironment that contributes to tumor progression and radio resistance. M2 TAMs are activated by the STAT6 signaling pathway. Therefore, we targeted STAT6 using an antisense oligonucleotide (ASO) along with hypofractionated RT (hRT; 3 fractions of 12 Gy each) to primary tumors in three bilateral murine NSCLC models (Lewis lung carcinoma, 344SQ-parental, and anti-PD-1-resistant 344SQ lung adenocarcinomas). We found that STAT6 ASO plus hRT slowed growth of both primary and abscopal tumors, decreased lung metastases, and extended survival. Interrogating the mechanism of action showed reduced M2 macrophage tumor infiltration, enhanced TH1 polarization, improved T-cell and macrophage function, and decreased TGFβ levels. The addition of anti-PD-1 further enhanced systemic antitumor responses. These results provide a preclinical rationale for the pursuit of an alternative therapeutic approach for patients with immune-resistant NSCLC.
Topics: Humans; Mice; Animals; Carcinoma, Non-Small-Cell Lung; Lung Neoplasms; Oligonucleotides, Antisense; Macrophages; Carcinoma, Lewis Lung; Tumor Microenvironment; STAT6 Transcription Factor
PubMed: 36700864
DOI: 10.1158/2326-6066.CIR-22-0547 -
JAMA Neurology Aug 2020An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
An unmet need remains for safe and efficacious treatments for Duchenne muscular dystrophy (DMD). To date, there are limited agents available that address the underlying cause of the disease.
OBJECTIVE
To evaluate the safety, tolerability, and efficacy of viltolarsen, a novel antisense oligonucleotide, in participants with DMD amenable to exon 53 skipping.
DESIGN, SETTING, AND PARTICIPANTS
This phase 2 study was a 4-week randomized clinical trial for safety followed by a 20-week open-label treatment period of patients aged 4 to 9 years with DMD amenable to exon 53 skipping. To enroll 16 participants, with 8 participants in each of the 2 dose cohorts, 17 participants were screened. Study enrollment occurred between December 16, 2016, and August 17, 2017, at sites in the US and Canada. Data were collected from December 2016 to February 2018, and data were analyzed from April 2018 to May 2019.
INTERVENTIONS
Participants received 40 mg/kg (low dose) or 80 mg/kg (high dose) of viltolarsen administered by weekly intravenous infusion.
MAIN OUTCOMES AND MEASURES
Primary outcomes of the trial included safety, tolerability, and de novo dystrophin protein production measured by Western blot in participants' biceps muscles. Secondary outcomes included additional assessments of dystrophin mRNA and protein production as well as clinical muscle strength and function.
RESULTS
Of the 16 included boys with DMD, 15 (94%) were white, and the mean (SD) age was 7.4 (1.8) years. After 20 to 24 weeks of treatment, significant drug-induced dystrophin production was seen in both viltolarsen dose cohorts (40 mg/kg per week: mean [range] 5.7% [3.2-10.3] of normal; 80 mg/kg per week: mean [range] 5.9% [1.1-14.4] of normal). Viltolarsen was well tolerated; no treatment-emergent adverse events required dose reduction, interruption, or discontinuation of the study drug. No serious adverse events or deaths occurred during the study. Compared with 65 age-matched and treatment-matched natural history controls, all 16 participants treated with viltolarsen showed significant improvements in timed function tests from baseline, including time to stand from supine (viltolarsen: -0.19 s; control: 0.66 s), time to run/walk 10 m (viltolarsen: 0.23 m/s; control: -0.04 m/s), and 6-minute walk test (viltolarsen: 28.9 m; control: -65.3 m) at the week 25 visit.
CONCLUSIONS AND RELEVANCE
Systemic treatment of participants with DMD with viltolarsen induced de novo dystrophin production, and clinical improvement of timed function tests was observed.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT02740972.
Topics: Child; Child, Preschool; Double-Blind Method; Dystrophin; Exons; Humans; Male; Muscular Dystrophy, Duchenne; Oligonucleotides; Oligonucleotides, Antisense; Outcome Assessment, Health Care
PubMed: 32453377
DOI: 10.1001/jamaneurol.2020.1264 -
Nucleic Acid Therapeutics Jun 2022Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some...
Antisense oligonucleotides are a relatively new therapeutic modality and safety evaluation is still a developing area of research. We have observed that some oligonucleotides can produce acute, nonhybridization dependent, neurobehavioral side effects after intracerebroventricular (ICV) dosing in mice. In this study, we use a combination of , , and bioinformatics approaches to identify a sequence design algorithm, which can reduce the number of acutely toxic molecules synthesized and tested in mice. We find a cellular assay measuring spontaneous calcium oscillations in neuronal cells can predict the behavioral side effects after ICV dosing, and may provide a mechanistic explanation for these observations. We identify sequence features that are overrepresented or underrepresented among oligonucleotides causing these reductions in calcium oscillations. A weighted linear combination of the five most informative sequence features predicts the outcome of ICV dosing with >80% accuracy. From this, we develop a bioinformatics tool that allows oligonucleotide designs with acceptable acute neurotoxic potential to be identified, thereby reducing the number of toxic molecules entering drug discovery pipelines. The informative sequence features we identified also suggest areas in which to focus future medicinal chemistry efforts.
Topics: Animals; Brain; Drug-Related Side Effects and Adverse Reactions; Mice; Oligonucleotides, Antisense
PubMed: 35166597
DOI: 10.1089/nat.2021.0071 -
Current Atherosclerosis Reports Feb 2020Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides... (Review)
Review
PURPOSE OF REVIEW
Atherosclerosis is characterized by accumulation of lipids and chronic inflammation in medium size to large arteries. Recently, RNA-based antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) are being developed, along with small molecule-based drugs and monoclonal antibodies, for the treatment of risk factors associated with atherosclerosis.. The purpose of this review is to describe nucleic acid-based therapeutics and introduce novel RNAs that might become future tools for treatment of atherosclerosis.
RECENT FINDINGS
RNA-based inhibitors for PCSK9, Lp(a), ApoCIII, and ANGPTL3 have been successfully tested in phase II-III clinical trials. Moreover, multiple microRNA and long non-coding RNAs have been found to reduce atherogenesis in preclinical animal models. Clinical trials especially with ASOs and siRNAs directed to liver, targeting cholesterol and lipoprotein metabolism, have shown promising results. Additional research in larger patient cohorts is needed to fully evaluate the therapeutic potential of these new drugs.
Topics: Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Animals; Anticholesteremic Agents; Apolipoprotein C-III; Atherosclerosis; Humans; Lipoprotein(a); Liver; MicroRNAs; Oligonucleotides, Antisense; PCSK9 Inhibitors; RNA, Long Noncoding; RNA, Small Interfering
PubMed: 32034521
DOI: 10.1007/s11883-020-0826-2 -
Cells Aug 2023Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most... (Review)
Review
Infectious diseases, particularly Tuberculosis (TB) caused by , pose a significant global health challenge, with 1.6 million reported deaths in 2021, making it the most fatal disease caused by a single infectious agent. The rise of drug-resistant infectious diseases adds to the urgency of finding effective and safe intervention therapies. Antisense therapy uses antisense oligonucleotides (ASOs) that are short, chemically modified, single-stranded deoxyribonucleotide molecules complementary to their mRNA target. Due to their designed target specificity and inhibition of a disease-causing gene at the mRNA level, antisense therapy has gained interest as a potential therapeutic approach. This type of therapy is currently utilized in numerous diseases, such as cancer and genetic disorders. Currently, there are limited but steadily increasing studies available that report on the use of ASOs as treatment for infectious diseases. This review explores the sustainability of FDA-approved and preclinically tested ASOs as a treatment for infectious diseases and the adaptability of ASOs for chemical modifications resulting in reduced side effects with improved drug delivery; thus, highlighting the potential therapeutic uses of ASOs for treating infectious diseases.
Topics: Humans; Communicable Diseases; Biological Therapy; Mycobacterium tuberculosis; Drug Delivery Systems; Oligonucleotides, Antisense; RNA, Messenger
PubMed: 37626929
DOI: 10.3390/cells12162119 -
Immunotherapy Nov 2017Alicaforsen is a 20-base antisense oligonucleotide inhibiting ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking... (Review)
Review
Alicaforsen is a 20-base antisense oligonucleotide inhibiting ICAM-1 production, which is an important adhesion molecule involved in leukocyte migration and trafficking to the site of inflammation. Hitherto, alicaforsen has been granted orphan drug designation and is prescribed as an unlicensed medicine in accordance with international regulation for the treatment of pouchitis and left-sided ulcerative colitis. Given the positive results evolving from one open-label trial and one case series in patients with chronic refractory pouchitis, US FDA has agreed to a rolling submission for a license application for the treatment of pouchitis, which has been recently initiated. Whether alicaforsen leads to higher endoscopic and clinical remission rates as placebo and whether the response can be maintained in the long-term in larger studies is yet unknown. An ongoing multicenter international Phase III trial will definitely address these unanswered questions.
Topics: Clinical Trials as Topic; Colitis, Ulcerative; Humans; Intercellular Adhesion Molecule-1; Oligonucleotides, Antisense; Phosphorothioate Oligonucleotides; Pouchitis; Treatment Outcome; United States; United States Food and Drug Administration
PubMed: 29067882
DOI: 10.2217/imt-2017-0085 -
RNA Biology 2018Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval... (Review)
Review
Therapeutics that directly target RNAs are promising for a broad spectrum of disorders, including the neurodegenerative diseases. This is exemplified by the FDA approval of Nusinersen, an antisense oligonucleotide (ASO) therapeutic for spinal muscular atrophy (SMA). RNA targeting therapeutics are currently under development for amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and spinocerebellar ataxias. We have used an ASO approach toward developing a treatment for spinocerebellar ataxia type 2 (SCA2), for targeting the causative gene ATXN2. We demonstrated that reduction of ATXN2 expression in SCA2 mice treated by intracerebroventicular injection (ICV) of ATXN2 ASO delayed motor phenotype onset, improved the expression of several genes demonstrated abnormally reduced by transcriptomic profiling of SCA2 mice, and restored abnormal Purkinje cell firing frequency in acute cerebellar sections. Here we discuss RNA abnormalities in disease and the prospects of targeting neurodegenerative diseases at the level of RNA control using ASOs and other RNA-targeted therapeutics.
Topics: Animals; Ataxin-2; Humans; Mice; Neurodegenerative Diseases; Oligonucleotides, Antisense
PubMed: 29560813
DOI: 10.1080/15476286.2018.1454812 -
Journal of Inherited Metabolic Disease Jan 2021Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence-specific manner, inducing targeted protein... (Review)
Review
Antisense oligonucleotide (AON) therapies involve short strands of modified nucleotides that target RNA in a sequence-specific manner, inducing targeted protein knockdown or restoration. Currently, 10 AON therapies have been approved in the United States and Europe. Nucleotides are chemically modified to protect AONs from degradation, enhance bioavailability and increase RNA affinity. Whereas single stranded AONs can efficiently be delivered systemically, delivery of double stranded AONs requires capsulation in lipid nanoparticles or binding to a conjugate as the uptake enhancing backbone is hidden in this conformation. With improved chemistry, delivery vehicles and conjugates, doses can be lowered, thereby reducing the risk and occurrence of side effects. AONs can be used to knockdown or restore levels of protein. Knockdown can be achieved by single stranded or double stranded AONs binding the RNA transcript and activating RNaseH-mediated and RISC-mediated degradation respectively. Transcript binding by AONs can also prevent translation, hence reducing protein levels. For protein restoration, single stranded AONs are used to modulate pre-mRNA splicing and either include or skip an exon to restore protein production. Intervening at a genetic level, AONs provide therapeutic options for inherited metabolic diseases as well. This review provides an overview of the different AON approaches, with a focus on AONs developed for inborn errors of metabolism.
Topics: Animals; Exons; Gene Knockdown Techniques; Humans; Nucleic Acid Conformation; Oligonucleotides, Antisense; RNA Splicing; RNA, Messenger
PubMed: 32391605
DOI: 10.1002/jimd.12251 -
Molecules and Cells Jan 2023Antisense oligonucleotide (ASO) technology has become an attractive therapeutic modality for various diseases, including Mendelian disorders. ASOs can modulate the... (Review)
Review
Antisense oligonucleotide (ASO) technology has become an attractive therapeutic modality for various diseases, including Mendelian disorders. ASOs can modulate the expression of a target gene by promoting mRNA degradation or changing pre-mRNA splicing, nonsense-mediated mRNA decay, or translation. Advances in medicinal chemistry and a deeper understanding of post-transcriptional mechanisms have led to the approval of several ASO drugs for diseases that had long lacked therapeutic options. For instance, an ASO drug called nusinersen became the first approved drug for spinal muscular atrophy, improving survival and the overall disease course. Mutations in the cystic fibrosis transmembrane conductance regulator () gene cause cystic fibrosis (CF). Although Trikafta and other CFTR-modulation therapies benefit most CF patients, there is a significant unmet therapeutic need for a subset of CF patients. In this review, we introduce ASO therapies and their mechanisms of action, describe the opportunities and challenges for ASO therapeutics for CF, and discuss the current state and prospects of ASO therapies for CF.
Topics: Humans; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Oligonucleotides, Antisense; Mutation; RNA Splicing
PubMed: 36697233
DOI: 10.14348/molcells.2023.2172