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Raguraman, Prithi, Tao Wang, Lixia Ma, Per Trolle Jørgensen, Jesper Wengel, and Rakesh N. Veedu. "Alpha-l-Locked Nucleic Acid-Modified Antisense Oligonucleotides Induce Efficient Splice Modulation In Vitro." International Journal of Molecular Sciences 21, no. 7 (March 31, 2020): 2434. http://dx.doi.org/10.3390/ijms21072434.
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Alpha-l-Locked nucleic acid (α-l-LNA) is a stereoisomeric analogue of locked nucleic acid (LNA), which possesses excellent biophysical properties and also exhibits high target binding affinity to complementary oligonucleotide sequences and resistance to nuclease degradations. Therefore, α-l-LNA nucleotides could be utilised to develop stable antisense oligonucleotides (AO), which can be truncated without compromising the integrity and efficacy of the AO. In this study, we explored the potential of α-l-LNA nucleotides-modified antisense oligonucleotides to modulate splicing by inducing Dmd exon-23 skipping in mdx mouse myoblasts in vitro. For this purpose, we have synthesised and systematically evaluated the efficacy of α-l-LNA-modified 2′-O-methyl phosphorothioate (2′-OMePS) AOs of three different sizes including 20mer, 18mer and 16mer AOs in parallel to fully-modified 2′-OMePS control AOs. Our results demonstrated that the 18mer and 16mer truncated AO variants showed slightly better exon-skipping efficacy when compared with the fully-23 modified 2′-OMePS control AOs, in addition to showing low cytotoxicity. As there was no previous report on using α-l-LNA-modified AOs in splice modulation, we firmly believe that this initial study could be beneficial to further explore and expand the scope of α-l-LNA-modified AO therapeutic molecules.
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Le, Bao T., Vyacheslav V. Filichev, and Rakesh N. Veedu. "Investigation of twisted intercalating nucleic acid (TINA)-modified antisense oligonucleotides for splice modulation by induced exon-skipping in vitro." RSC Advances 6, no. 97 (2016): 95169–72. http://dx.doi.org/10.1039/c6ra22346j.
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Flynn, Loren L., Chalermchai Mitrpant, Abbie Adams, Ianthe L. Pitout, Anja Stirnweiss, Sue Fletcher, and Steve D. Wilton. "Targeted SMN Exon Skipping: A Useful Control to Assess In Vitro and In Vivo Splice-Switching Studies." Biomedicines 9, no. 5 (May 14, 2021): 552. http://dx.doi.org/10.3390/biomedicines9050552.
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The literature surrounding the use of antisense oligonucleotides continues to grow, with new disease and mechanistic applications constantly evolving. Furthermore, the discovery and advancement of novel chemistries continues to improve antisense delivery, stability and effectiveness. For each new application, a rational sequence design is recommended for each oligomer, as is chemistry and delivery optimization. To confirm oligomer delivery and antisense activity, a positive control AO sequence with well characterized target-specific effects is recommended. Here, we describe splice-switching antisense oligomer sequences targeting the ubiquitously expressed human and mouse SMN and Smn genes for use as control AOs for this purpose. We report two AO sequences that induce targeted skipping of SMN1/SMN2 exon 7 and two sequences targeting the Smn gene, that induce skipping of exon 5 and exon 7. These antisense sequences proved effective in inducing alternative splicing in both in vitro and in vivo models and are therefore broadly applicable as controls. Not surprisingly, we discovered a number of differences in efficiency of exon removal between the two species, further highlighting the differences in splice regulation between species.
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Lim, Kenji Rowel Q., Rika Maruyama, Yusuke Echigoya, Quynh Nguyen, Aiping Zhang, Hunain Khawaja, Sreetama Sen Chandra, et al. "Inhibition ofDUX4expression with antisense LNA gapmers as a therapy for facioscapulohumeral muscular dystrophy." Proceedings of the National Academy of Sciences 117, no. 28 (June 29, 2020): 16509–15. http://dx.doi.org/10.1073/pnas.1909649117.
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Facioscapulohumeral muscular dystrophy (FSHD), characterized by progressive muscle weakness and deterioration, is genetically linked to aberrant expression ofDUX4in muscle. DUX4, in its full-length form, is cytotoxic in nongermline tissues. Here, we designed locked nucleic acid (LNA) gapmer antisense oligonucleotides (AOs) to knock downDUX4in immortalized FSHD myoblasts and theFLExDUX4FSHD mouse model. Using a screening method capable of reliably evaluating the knockdown efficiency of LNA gapmers against endogenousDUX4messenger RNA in vitro, we demonstrate that several designed LNA gapmers selectively and effectively reducedDUX4expression with nearly complete knockdown. We also found potential functional benefits of AOs on muscle fusion and structure in vitro. Finally, we show that one of the LNA gapmers was taken up and induced effective silencing ofDUX4upon local treatment in vivo. The LNA gapmers developed here will help facilitate the development of FSHD therapies.
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Chakravarthy, Madhuri, Suxiang Chen, Tao Wang, and Rakesh N. Veedu. "Development of Novel Chemically-Modified Nucleic Acid Molecules for Efficient Inhibition of Human MAPT Gene Expression." Genes 11, no. 6 (June 19, 2020): 667. http://dx.doi.org/10.3390/genes11060667.
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The hyperphosphorylation of the microtubule-associated protein tau (MAPT) has been implicated in various neurological diseases, including Alzheimer’s disease. It has been hypothesized that the reduction of MAPT would result in depolymerizing neurofibrillary tangles and could be a potential strategy for the treatment of Alzheimer’s disease and other tauopathies. In this study, we report the development of novel DNAzymes and splice-modulating antisense oligonucleotides (AOs) for the efficient inhibition of MAPT. We designed and synthesized a range of DNAzymes and 2ʹ-O-methyl (2’-OMe)-modified AOs on a phosphorothioate (PS) backbone targeting various exons across the MAPT gene transcript. Our results demonstrated that RNV563, an arm-loop-arm-type DNAzyme targeting exon 13, and an AO candidate AO4, targeting exon 4, efficiently downregulated MAPT RNA expression by 58% and 96%, respectively. In addition, AO4 also reduced the MAPT protein level by 74%. In line with our results, we believe that AO4 could be used as a potential therapeutic molecule for Alzheimer’s disease and other tauopathies.
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Božič, Tim, Matja Zalar, Boris Rogelj, Janez Plavec, and Primož Šket. "Structural Diversity of Sense and Antisense RNA Hexanucleotide Repeats Associated with ALS and FTLD." Molecules 25, no. 3 (January 25, 2020): 525. http://dx.doi.org/10.3390/molecules25030525.
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The hexanucleotide expansion GGGGCC located in C9orf72 gene represents the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar dementia (FTLD). Since the discovery one of the non-exclusive mechanisms of expanded hexanucleotide G4C2 repeats involved in ALS and FTLD is RNA toxicity, which involves accumulation of pathological sense and antisense RNA transcripts. Formed RNA foci sequester RNA-binding proteins, causing their mislocalization and, thus, diminishing their biological function. Therefore, structures adopted by pathological RNA transcripts could have a key role in pathogenesis of ALS and FTLD. Utilizing NMR spectroscopy and complementary methods, we examined structures adopted by both guanine-rich sense and cytosine-rich antisense RNA oligonucleotides with four hexanucleotide repeats. While both oligonucleotides tend to form dimers and hairpins, the equilibrium of these structures differs with antisense oligonucleotide being more sensitive to changes in pH and sense oligonucleotide to temperature. In the presence of K+ ions, guanine-rich sense RNA oligonucleotide also adopts secondary structures called G-quadruplexes. Here, we also observed, for the first time, that antisense RNA oligonucleotide forms i-motifs under specific conditions. Moreover, simultaneous presence of sense and antisense RNA oligonucleotides promotes formation of heterodimer. Studied structural diversity of sense and antisense RNA transcripts not only further depicts the complex nature of neurodegenerative diseases but also reveals potential targets for drug design in treatment of ALS and FTLD.
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Martz, Lauren. "ALS antisense oligonucleotides." Science-Business eXchange 6, no. 43 (November 2013): 1210. http://dx.doi.org/10.1038/scibx.2013.1210.
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Chakravarthy and Veedu. "BACE1 Inhibition Using 2’-OMePS Steric Blocking Antisense Oligonucleotides." Genes 10, no. 9 (September 12, 2019): 705. http://dx.doi.org/10.3390/genes10090705.
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Amyloid beta-peptide is produced by the cleavage of amyloid precursor protein by two secretases, a β-secretase, beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) and a γ-secretase. It has been hypothesised that partial inhibition of BACE1 in individuals with a high risk of developing Alzheimer’s disease may be beneficial in preventing cognitive decline. In this study, we report the development of a novel antisense oligonucleotide (AO) that could efficiently downregulate the BACE1 transcript and partially inhibit BACE1 protein. We designed and synthesised a range of 2’-OMethyl-modified antisense oligonucleotides with a phosphorothioate backbone across various exons of the BACE1 transcript, of which AO2, targeting exon 2, efficiently downregulated BACE1 RNA expression by 90%. The sequence of AO2 was later synthesised with a phosphorodiamidate morpholino chemistry, which was found to be not as efficient at downregulating BACE1 expression as the 2’-OMethyl antisense oligonucleotides with a phosphorothioate backbone variant. AO2 also reduced BACE1 protein levels by 45%. In line with our results, we firmly believe that AO2 could be used as a potential preventative therapeutic strategy for Alzheimer’s disease.
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Fekete, Béla, János Sági, Attila Szemzõ, László Kovács, Katalin Pálóczi, Valéria L. Varga, Klára Tamássy, and András Falus. "Inhibition of IgE production by epsilon (ϵ) chain-specific antisense oligonucleotides (AOs) studied on human myeloma cell line U266 and peripheral blood mononuclear cells of a patient with hypereosinophilia." Immunology Letters 58, no. 3 (August 1997): 181–90. http://dx.doi.org/10.1016/s0165-2478(97)00082-5.
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Prasad, Vikram, Shehla Hashim, Amitabha Mukhopadhyay, Sandip K. Basu, and Rajendra P. Roy. "Oligonucleotides Tethered to a Short Polyguanylic Acid Stretch Are Targeted to Macrophages: Enhanced Antiviral Activity of a Vesicular Stomatitis Virus-Specific Antisense Oligonucleotide." Antimicrobial Agents and Chemotherapy 43, no. 11 (November 1, 1999): 2689–96. http://dx.doi.org/10.1128/aac.43.11.2689.
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ABSTRACT The poor membrane permeability of oligonucleotides is one of the major problems of antisense technology. Here we report the construction of designer oligonucleotides for targeted delivery to macrophages. The oligonucleotides tethered to a 10-mer poly(G) sequence at their 3′ ends were recognized by scavenger receptors on macrophages and were taken up about 8- to 10-fold as efficiently as those oligonucleotides that either lacked a poly(G) tail or that contained a 10-mer poly(C) tail instead of the poly(G) tail. The enhanced uptake of poly(G) constructs was inhibited in the presence of poly(G) and other known ligands of the scavenger receptor. The bioefficacy of poly(G)-mediated targeting of antisense oligonucleotides (ANS) was demonstrated by using vesicular stomatitis virus (VSV) as a model system. The ability of ANS directed against the translation initiation site of N protein mRNA of VSV to inhibit virus replication was assessed. The ANS with the 10-mer poly(G) sequences (ANS-G) brought about significant inhibition of VSV replication in J774E cells (a murine monocyte/macrophage cell line) and Chinese hamster ovary (CHO) cell transfectants expressing scavenger receptors. The ANS lacking a 10-mer poly(G) stretch were ineffective. The inhibition of VSV replication due to ANS-G was completely abrogated in the presence of 10-mer poly(G), indicating that the antisense effect of the ANS-G molecule was a consequence of scavenger receptor-mediated enhanced uptake. Importantly, antisense molecules linked exclusively by natural phosphodiester bonds were as bioeffective as those synthesized with a mixed backbone of phosphodiester and phosphorothioate. Taken together, these results suggest that macrophage-directed designer ANS against infective agents may simply be obtained by adding a short stretch of guanylic acid sequence to the desired specific ANS during solid-phase synthesis. This nucleic acid-based strategy, which utilizes homogeneous preparation of ANS, may find applications in directed manipulation of macrophage metabolism for a variety of purposes as well as in therapy of a broad spectrum of macrophage-related disorders amenable to the antisense approach.
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Fernandes, Stephanie A., Andrew G. L. Douglas, Miguel A. Varela, Matthew J. A. Wood, and Yoshitsugu Aoki. "Oligonucleotide-Based Therapy for FTD/ALS Caused by theC9orf72Repeat Expansion: A Perspective." Journal of Nucleic Acids 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/208245.
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Amyotrophic lateral sclerosis (ALS) is a progressive and lethal disease of motor neuron degeneration, leading to paralysis of voluntary muscles and death by respiratory failure within five years of onset. Frontotemporal dementia (FTD) is characterised by degeneration of frontal and temporal lobes, leading to changes in personality, behaviour, and language, culminating in death within 5–10 years. Both of these diseases form a clinical, pathological, and genetic continuum of diseases, and this link has become clearer recently with the discovery of a hexanucleotide repeat expansion in theC9orf72gene that causes the FTD/ALS spectrum, that is, c9FTD/ALS. Two basic mechanisms have been proposed as being potentially responsible for c9FTD/ALS: loss-of-function of the protein encoded by this gene (associated with aberrant DNA methylation) and gain of function through the formation of RNAfocior protein aggregates. These diseases currently lack any cure or effective treatment. Antisense oligonucleotides (ASOs) are modified nucleic acids that are able to silence targeted mRNAs or perform splice modulation, and the fact that they have proved efficient in repeat expansion diseases including myotonic dystrophy type 1 makes them ideal candidates for c9FTD/ALS therapy. Here, we discuss potential mechanisms and challenges for developing oligonucleotide-based therapy for c9FTD/ALS.
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Lin, Mengsi, Xinyi Hu, Shiyi Chang, Yan Chang, Wenjun Bian, Ruikun Hu, Jing Wang, Qingwen Zhu, and Jiaying Qiu. "Advances of Antisense Oligonucleotide Technology in the Treatment of Hereditary Neurodegenerative Diseases." Evidence-Based Complementary and Alternative Medicine 2021 (June 10, 2021): 1–9. http://dx.doi.org/10.1155/2021/6678422.
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Antisense nucleic acids are single-stranded oligonucleotides that have been specially chemically modified, which can bind to RNA expressed by target genes through base complementary pairing and affect protein synthesis at the level of posttranscriptional processing or protein translation. In recent years, the application of antisense nucleic acid technology in the treatment of neuromuscular diseases has made remarkable progress. In 2016, the US FDA approved two antisense nucleic acid drugs for the treatment of Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), and the development to treat other neurodegenerative diseases has also entered the clinical stage. Therefore, ASO represents a treatment with great potential. The article will summarize ASO therapies in terms of mechanism of action, chemical modification, and administration methods and analyze their role in several common neurodegenerative diseases, such as SMA, DMD, and amyotrophic lateral sclerosis (ALS). This article systematically summarizes the great potential of antisense nucleic acid technology in the treatment of hereditary neurodegenerative diseases.
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Miller, Timothy, Merit Cudkowicz, Pamela J. Shaw, Peter M. Andersen, Nazem Atassi, Robert C. Bucelli, Angela Genge, et al. "Phase 1–2 Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS." New England Journal of Medicine 383, no. 2 (July 9, 2020): 109–19. http://dx.doi.org/10.1056/nejmoa2003715.
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Riboldi, Giulietta, Chiara Zanetta, Michela Ranieri, Monica Nizzardo, Chiara Simone, Francesca Magri, Nereo Bresolin, Giacomo P. Comi, and Stefania Corti. "Antisense Oligonucleotide Therapy for the Treatment of C9ORF72 ALS/FTD Diseases." Molecular Neurobiology 50, no. 3 (May 9, 2014): 721–32. http://dx.doi.org/10.1007/s12035-014-8724-7.
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Marc, Gotkine, Rozenstein Leah, Einstein Ofira, Abramsky Oded, Argov Zohar, and Rosenmann Hanna. "Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice." BioMed Research International 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/845345.
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Objective. Previous research suggests that acetylcholinesterase (AChE) may be involved in ALS pathogenesis. AChE enzyme inhibitors can upregulate AChE transcription which in certain contexts can have deleterious (noncatalytic) effects, making them theoretically harmful in ALS, whilst AChE antisense-oligonucleotides (mEN101), which downregulate AChE may be beneficial. Our aim was to investigate whether downregulation of AChE using mEN101 is beneficial in an ALS mouse model.Methods. ALS (G93A-SOD1) mice received saline, mEN101, inverse-EN101, or neostigmine. Treatments were administered from 5 weeks. Disease-onset and survival were recorded. Additional mice were sacrificed for pathological analysis at 15 weeks of age. In a follow-up experiment treatment was started at the symptomatic stage at a higher dose.Results. mEN101 given at the presymptomatic (but not symptomatic) stage prolonged survival and attenuated motor-neuron loss in ALS mice. In contrast, neostigmine exacerbated the clinical parameters.Conclusions. These results suggest that AChE may be involved in ALS pathogenesis. The accelerated disease course with neostigmine suggests that any beneficial effects of mEN101 occur through a non-catalytic rather than cholinergic mechanism.
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McCampbell, Alex, Tracy Cole, Amy J. Wegener, Giulio S. Tomassy, Amy Setnicka, Brandon J. Farley, Kathleen M. Schoch, et al. "Antisense oligonucleotides extend survival and reverse decrement in muscle response in ALS models." Journal of Clinical Investigation 128, no. 8 (July 16, 2018): 3558–67. http://dx.doi.org/10.1172/jci99081.
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Cappella, Marisa, Chiara Ciotti, Mathilde Cohen-Tannoudji, and Maria Grazia Biferi. "Gene Therapy for ALS—A Perspective." International Journal of Molecular Sciences 20, no. 18 (September 6, 2019): 4388. http://dx.doi.org/10.3390/ijms20184388.
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Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease (MND) with no cure. Recent advances in gene therapy open a new perspective to treat this disorder—particularly for the characterized genetic forms. Gene therapy approaches, involving the delivery of antisense oligonucleotides into the central nervous system (CNS) are being tested in clinical trials for patients with mutations in SOD1 or C9orf72 genes. Viral vectors can be used to deliver therapeutic sequences to stably transduce motor neurons in the CNS. Vectors derived from adeno-associated virus (AAV), can efficiently target genes and have been tested in several pre-clinical settings with promising outcomes. Recently, the Food and Drug Administration (FDA) approved Zolgensma, an AAV-mediated treatment for another MND—the infant form of spinal muscular atrophy. Given the accelerated progress in gene therapy, it is potentially a promising avenue to develop an efficient and safe cure for ALS.
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Gotkine, Marc, Leah Rozenstein, Ofira Einstein, Oded Abramsky, Zohar Argov, and Hanna Rosenmann. "Corrigendum to “Presymptomatic Treatment with Acetylcholinesterase Antisense Oligonucleotides Prolongs Survival in ALS (G93A-SOD1) Mice”." BioMed Research International 2015 (2015): 1. http://dx.doi.org/10.1155/2015/651934.
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Trainer, Peter J., John D. C. Newell-Price, John Ayuk, Simon J. B. Aylwin, Aled Rees, William Drake, Philippe Chanson, et al. "A randomised, open-label, parallel group phase 2 study of antisense oligonucleotide therapy in acromegaly." European Journal of Endocrinology 179, no. 2 (August 2018): 97–108. http://dx.doi.org/10.1530/eje-18-0138.
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Objective ATL1103 is a second-generation antisense oligomer targeting the human growth hormone (GH) receptor. This phase 2 randomised, open-label, parallel-group study assessed the potential of ATL1103 as a treatment for acromegaly. Design Twenty-six patients with active acromegaly (IGF-I >130% upper limit of normal) were randomised to subcutaneous ATL1103 200 mg either once or twice weekly for 13 weeks and monitored for a further 8-week washout period. Methods The primary efficacy measures were change in IGF-I at week 14, compared to baseline and between cohorts. For secondary endpoints (IGFBP3, acid labile subunit (ALS), GH, growth hormone-binding protein (GHBP)), comparison was between baseline and week 14. Safety was assessed by reported adverse events. Results and conclusions Baseline median IGF-I was 447 and 649 ng/mL in the once- and twice-weekly groups respectively. Compared to baseline, at week 14, twice-weekly ATL1103 resulted in a median fall in IGF-I of 27.8% (P = 0.0002). Between cohort comparison at week 14 demonstrated the median fall in IGF-I to be 25.8% (P = 0.0012) greater with twice-weekly dosing. In the twice-weekly cohort, IGF-I was still declining at week 14, and remained lower at week 21 than at baseline by a median of 18.7% (P = 0.0005). Compared to baseline, by week 14, IGFBP3 and ALS had declined by a median of 8.9% (P = 0.027) and 16.7% (P = 0.017) with twice-weekly ATL1103; GH had increased by a median of 46% at week 14 (P = 0.001). IGFBP3, ALS and GH did not change with weekly ATL1103. GHBP fell by a median of 23.6% and 48.8% in the once- and twice-weekly cohorts (P = 0.027 and P = 0.005) respectively. ATL1103 was well tolerated, although 84.6% of patients experienced mild-to-moderate injection-site reactions. This study provides proof of concept that ATL1103 is able to significantly lower IGF-I in patients with acromegaly.
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Cappella, Marisa, Pierre-François Pradat, Giorgia Querin, and Maria Grazia Biferi. "Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy." Journal of Neuromuscular Diseases 8, no. 1 (January 1, 2021): 25–38. http://dx.doi.org/10.3233/jnd-200531.
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Amyotrophic lateral sclerosis (ALS) is a devastating and incurable motor neuron (MN) disorder affecting both upper and lower MNs. Despite impressive advances in the understanding of the disease’s pathological mechanism, classical pharmacological clinical trials failed to provide an efficient cure for ALS over the past twenty years. Two different gene therapy approaches were recently approved for the monogenic disease Spinal muscular atrophy, characterized by degeneration of lower MNs. This milestone suggests that gene therapy-based therapeutic solutions could be effective for the treatment of ALS. This review summarizes the possible reasons for the failure of traditional clinical trials for ALS. It provides then a focus on the advent of gene therapy approaches for hereditary forms of ALS. Specifically, it describes clinical use of antisense oligonucleotides in three familial forms of ALS, caused by mutations in SOD1, C9orf72 and FUS genes, respectively.. Clinical and pre-clinical studies based on AAV-mediated gene therapy approaches for both familial and sporadic ALS cases are presented as well. Overall, this overview highlights the potential of gene therapy as a transforming technology that will have a huge impact on treatment perspective for ALS patients and on the design of future clinical trials.
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Jiang, Jie, Qiang Zhu, Tania F. Gendron, Shahram Saberi, Melissa McAlonis-Downes, Amanda Seelman, Jennifer E. Stauffer, et al. "Gain of Toxicity from ALS/FTD-Linked Repeat Expansions in C9ORF72 Is Alleviated by Antisense Oligonucleotides Targeting GGGGCC-Containing RNAs." Neuron 90, no. 3 (May 2016): 535–50. http://dx.doi.org/10.1016/j.neuron.2016.04.006.
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Babić Leko, Mirjana, Vera Župunski, Jason Kirincich, Dinko Smilović, Tibor Hortobágyi, Patrick R. Hof, and Goran Šimić. "Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion." Behavioural Neurology 2019 (January 15, 2019): 1–18. http://dx.doi.org/10.1155/2019/2909168.
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Two clinically distinct diseases, amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), have recently been classified as two extremes of the FTD/ALS spectrum. The neuropathological correlate of FTD is frontotemporal lobar degeneration (FTLD), characterized by tau-, TDP-43-, and FUS-immunoreactive neuronal inclusions. An earlier discovery that a hexanucleotide repeat expansion mutation in chromosome 9 open reading frame 72 (C9orf72) gene causes ALS and FTD established a special subtype of ALS and FTLD with TDP-43 pathology (C9FTD/ALS). Normal individuals carry 2–10 hexanucleotide GGGGCC repeats in the C9orf72 gene, while more than a few hundred repeats represent a risk for ALS and FTD. The proposed molecular mechanisms by which C9orf72 repeat expansions induce neurodegenerative changes are C9orf72 loss-of-function through haploinsufficiency, RNA toxic gain-of-function, and gain-of-function through the accumulation of toxic dipeptide repeat proteins. However, many more cellular processes are affected by pathological processes in C9FTD/ALS, including nucleocytoplasmic transport, RNA processing, normal function of nucleolus, formation of membraneless organelles, translation, ubiquitin proteasome system, Notch signalling pathway, granule transport, and normal function of TAR DNA-binding protein 43 (TDP-43). Although the exact molecular mechanisms through which C9orf72 repeat expansions account for neurodegeneration have not been elucidated, some potential therapeutics, such as antisense oligonucleotides targeting hexanucleotide GGGGCC repeats in mRNA, were successful in preclinical trials and are awaiting phase 1 clinical trials. In this review, we critically discuss each proposed mechanism and provide insight into the most recent studies aiming to elucidate the molecular underpinnings of C9FTD/ALS.
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Scoles, Daniel R., Warunee Dansithong, Lance T. Pflieger, Sharan Paul, Mandi Gandelman, Karla P. Figueroa, Frank Rigo, C. Frank Bennett, and Stefan M. Pulst. "ALS-associated genes in SCA2 mouse spinal cord transcriptomes." Human Molecular Genetics 29, no. 10 (April 20, 2020): 1658–72. http://dx.doi.org/10.1093/hmg/ddaa072.
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Abstract The spinocerebellar ataxia type 2 (SCA2) gene ATXN2 has a prominent role in the pathogenesis and treatment of amyotrophic lateral sclerosis (ALS). In addition to cerebellar ataxia, motor neuron disease is often seen in SCA2, and ATXN2 CAG repeat expansions in the long normal range increase ALS risk. Also, lowering ATXN2 expression in TDP-43 ALS mice prolongs their survival. Here we investigated the ATXN2 relationship with motor neuron dysfunction in vivo by comparing spinal cord (SC) transcriptomes reported from TDP-43 and SOD1 ALS mice and ALS patients with those from SCA2 mice. SC transcriptomes were determined using an SCA2 bacterial artificial chromosome mouse model expressing polyglutamine expanded ATXN2. SCA2 cerebellar transcriptomes were also determined, and we also investigated the modification of gene expression following treatment of SCA2 mice with an antisense oligonucleotide (ASO) lowering ATXN2 expression. Differentially expressed genes (DEGs) defined three interconnected pathways (innate immunity, fatty acid biosynthesis and cholesterol biosynthesis) in separate modules identified by weighted gene co-expression network analysis. Other key pathways included the complement system and lysosome/phagosome pathways. Of all DEGs in SC, 12.6% were also dysregulated in the cerebellum. Treatment of mice with an ATXN2 ASO also modified innate immunity, the complement system and lysosome/phagosome pathways. This study provides new insights into the underlying molecular basis of SCA2 SC phenotypes and demonstrates annotated pathways shared with TDP-43 and SOD1 ALS mice and ALS patients. It also emphasizes the importance of ATXN2 in motor neuron degeneration and confirms ATXN2 as a therapeutic target.
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Hotte, S. J., E. Y. Yu, H. W. Hirte, C. S. Higano, M. Gleave, and K. N. Chi. "OGX-427, a 2'methoxyethyl antisense oligonucleotide (ASO), against HSP27: Results of a first-in-human trial." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 3506. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.3506.
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3506 Background: Heat shock protein 27 (Hsp27) is a chaperone protein expressed in many cancers and implicated as a therapeutic “hyper-node” affecting multiple pathways in cancer progression. Overexpression of Hsp27 confers a resistant phenotype. OGX-427 is a second generation ASO that inhibits Hsp27 expression which in preclinical models inhibited cell growth, induced apoptosis, and enhanced chemotherapy efficacy. The purpose of this phase 1 study was to determine the recommended phase 2 dose of OGX-427 alone and in combination with docetaxel. Methods: Eligible patients (pts) had to have metastatic breast, ovarian, prostate, NSCLC, or bladder cancer. OGX-427 was administered IV weekly on a 21-day cycle after 3 loading doses (LD) within 9 days. OGX-427 was escalated over 5 planned dose levels (DL) (200, 400, 600, 800, 1,000 mg), with 6 pts/DL. Plasma PK and serial ECGs were performed in cycle 1. Circulating tumor cells (CTC), Hsp27+ CTC and serum Hsp27 levels were evaluated serially. Results: 34 pts have been accrued and single agent dose escalation is complete. Median age was 62 (range: 33–86) yrs; 16 pts had prostate, 10 breast, 5 ovary and 3 lung ca. Median cycles administered were 2 (0–8) with 2 pts remaining on treatment. Most common related AEs: chills (53%), pruritis (29%), flushing (21%), elevated creatinine (18%), fatigue (15%), arthralgia (15%). More than 80% of pts had grade (Gr) 1/2 infusion reactions during the LDs or C1. One pt on 1,000 mg DL was hospitalized with Gr 3 infusion reaction. Gr 3 elevations of PTT (with normal INR) were seen in >50% of pts on 800 and 1,000 mg DL. At 600 mg DL, one pt had a Gr 3 epistaxis and one pt had a DLT with a Gr 3 cerebral bleed into a metastasis. No significant QTcF changes were observed. Three pts with prostate ca had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28%, and 41%. Five pts have had stable disease for >3 months. Preliminary mean PK data for 200–600 mg DLs: T1/2 = 2.8–3.1 hrs, peak concentration = 21,756 - 102,591 ng/mL and AUCinf ranged from 63,552 - 328,153 ng.h/mL, increasing with dose. Declines in CTC and Hsp27+ CTC have been observed at all DL. Conclusions: OGX-427 was well tolerated. Toxicity consisted mainly of infusion reactions and transient PTT changes. Changes in tumor markers suggest single-agent activity. [Table: see text]
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Oettle, H., T. Seufferlein, R. Schmid, T. Luger, S. Ludwig, S. Schmaus, M. Beyer, D. Fischer, M. Hafner, and K. Schlingensiepen. "Targeted tumor therapy with the TGF-beta2 antisense compound AP 12009 for the treatment of advanced solid tumors." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 14012. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.14012.
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14012 Background: TGF-β overexpression in advanced tumors is correlated with tumor-induced immunosuppression, proliferation and angiogenesis. Furthermore, it is a key factor for induction of epithelial to mesenchymal transition (EMT), thus promoting invasion and metastasis. Targeted tumor therapy by an antisense oligonucleotide has already been proven to be successful in tumor therapy: AP 12009, a TGF-β2-mRNA-specific antisense oligodeoxynucleotide, has shown strong clinical indication of efficacy including complete and lasting remissions in malignant glioma. Methods: Spurred by the highly encouraging clinical data in malignant glioma and strong anti-tumor activity in a wide variety of preclinical assays, clinical studies in further indications were initiated. A multi-center dose-escalation phase I/II trial with AP 12009 in patients suffering from advanced solid tumors was started in 2005. Primary endpoint is to assess the maximum tolerated dose (MTD) as well as the dose-limiting toxicity (DLT). AP 12009 is administered i.v. in 14-day cycles. Results: Preclinically, in human pancreatic cancer and melanoma cell cultures AP 12009 significantly reduced the TGF-β2 secretion of cancer cells, inhibited tumor cell proliferation, and blocked migration of cancer cells. Additionally, AP 12009 reversed TGF-β2 mediated immunosuppression induced by pancreatic carcinoma cells. In the ongoing clinical phase I/II dose-escalation study, two cohorts of tumor patients have already been treated intravenously with AP 12009 as of Dec 2005. Further dose escalations are ongoing. So far, no DLT, no possibly related SAEs and only seven possibly related AEs were observed. MTD is not yet reached. The majority of patients received more than the minimum number of two cycles, one of them received ten full cycles. First signs of efficacy could also be observed. Conclusions: In conclusion, the preclinical results with pancreatic cancer and malignant melanoma cell cultures as well as the successful clinical application of AP 12009 in the lead indication malignant glioma form a rational basis for the use of the antisense compound AP 12009 as targeted therapy of advanced, TGF-β2 overexpressing tumors. [Table: see text]
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Cook, Casey N., Yanwei Wu, Hana M. Odeh, Tania F. Gendron, Karen Jansen-West, Giulia del Rosso, Mei Yue, et al. "C9orf72 poly(GR) aggregation induces TDP-43 proteinopathy." Science Translational Medicine 12, no. 559 (September 2, 2020): eabb3774. http://dx.doi.org/10.1126/scitranslmed.abb3774.
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TAR DNA-binding protein 43 (TDP-43) inclusions are a pathological hallmark of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), including cases caused by G4C2 repeat expansions in the C9orf72 gene (c9FTD/ALS). Providing mechanistic insight into the link between C9orf72 mutations and TDP-43 pathology, we demonstrated that a glycine-arginine repeat protein [poly(GR)] translated from expanded G4C2 repeats was sufficient to promote aggregation of endogenous TDP-43. In particular, toxic poly(GR) proteins mediated sequestration of full-length TDP-43 in an RNA-independent manner to induce cytoplasmic TDP-43 inclusion formation. Moreover, in GFP-(GR)200 mice, poly(GR) caused the mislocalization of nucleocytoplasmic transport factors and nuclear pore complex proteins. These mislocalization events resulted in the aberrant accumulation of endogenous TDP-43 in the cytoplasm where it co-aggregated with poly(GR). Last, we demonstrated that treating G4C2 repeat–expressing mice with repeat-targeting antisense oligonucleotides lowered poly(GR) burden, which was accompanied by reduced TDP-43 pathology and neurodegeneration, including lowering of plasma neurofilament light (NFL) concentration. These results contribute to clarification of the mechanism by which poly(GR) drives TDP-43 proteinopathy, confirm that G4C2-targeted therapeutics reduce TDP-43 pathology in vivo, and demonstrate that alterations in plasma NFL provide insight into the therapeutic efficacy of disease-modifying treatments.
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Karpe, Yashashree, Zhenyu Chen, and Xue-Jun Li. "Stem Cell Models and Gene Targeting for Human Motor Neuron Diseases." Pharmaceuticals 14, no. 6 (June 12, 2021): 565. http://dx.doi.org/10.3390/ph14060565.
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Motor neurons are large projection neurons classified into upper and lower motor neurons responsible for controlling the movement of muscles. Degeneration of motor neurons results in progressive muscle weakness, which underlies several debilitating neurological disorders including amyotrophic lateral sclerosis (ALS), hereditary spastic paraplegias (HSP), and spinal muscular atrophy (SMA). With the development of induced pluripotent stem cell (iPSC) technology, human iPSCs can be derived from patients and further differentiated into motor neurons. Motor neuron disease models can also be generated by genetically modifying human pluripotent stem cells. The efficiency of gene targeting in human cells had been very low, but is greatly improved with recent gene editing technologies such as zinc-finger nucleases (ZFN), transcription activator-like effector nucleases (TALEN), and CRISPR-Cas9. The combination of human stem cell-based models and gene editing tools provides unique paradigms to dissect pathogenic mechanisms and to explore therapeutics for these devastating diseases. Owing to the critical role of several genes in the etiology of motor neuron diseases, targeted gene therapies have been developed, including antisense oligonucleotides, viral-based gene delivery, and in situ gene editing. This review summarizes recent advancements in these areas and discusses future challenges toward the development of transformative medicines for motor neuron diseases.
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Muratet, François, Elisa Teyssou, Aude Chiot, Séverine Boillée, Christian S. Lobsiger, Delphine Bohl, Beata Gyorgy, et al. "Impact of a frequent nearsplice SOD1 variant in amyotrophic lateral sclerosis: optimising SOD1 genetic screening for gene therapy opportunities." Journal of Neurology, Neurosurgery & Psychiatry 92, no. 9 (March 30, 2021): 942–49. http://dx.doi.org/10.1136/jnnp-2020-325921.
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ObjectiveMutations in superoxide dismutase 1 gene (SOD1), encoding copper/zinc superoxide dismutase protein, are the second most frequent high penetrant genetic cause for amyotrophic lateral sclerosis (ALS) motor neuron disease in populations of European descent. More than 200 missense variants are reported along the SOD1 protein. To limit the production of these aberrant and deleterious SOD1 species, antisense oligonucleotide approaches have recently emerged and showed promising effects in clinical trials. To offer the possibility to any patient with SOD1-ALS to benefit of such a gene therapy, it is necessary to ascertain whether any variant of unknown significance (VUS), detected for example in SOD1 non-coding sequences, is pathogenic.MethodsWe analysed SOD1 mutation distribution after SOD1 sequencing in a large cohort of 470 French familial ALS (fALS) index cases.ResultsWe identified a total of 27 SOD1 variants in 38 families including two SOD1 variants located in nearsplice or intronic regions of the gene. The pathogenicity of the c.358–10T>G nearsplice SOD1 variant was corroborated based on its high frequency (as the second most frequent SOD1 variant) in French fALS, the segregation analysis confirmed in eight affected members of a large pedigree, the typical SOD1-related phenotype observed (with lower limb onset and prominent lower motor neuron involvement), and findings on postmortem tissues showing SOD1 misaccumulation.ConclusionsOur results highlighted nearsplice/intronic mutations in SOD1 are responsible for a significant portion of French fALS and suggested the systematic analysis of the SOD1 mRNA sequence could become the method of choice for SOD1 screening, not to miss these specific cases.
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Zhou, Tong, Xianhong Meng, Hui Che, Nannan Shen, Dan Xiao, Xiaotong Song, Meihua Liang, et al. "Regulation of Insulin Resistance by Multiple MiRNAs via Targeting the GLUT4 Signalling Pathway." Cellular Physiology and Biochemistry 38, no. 5 (2016): 2063–78. http://dx.doi.org/10.1159/000445565.
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Background/Aims: Type 2 Diabetes Mellitus (T2DM) is characterized by insulin resistance (IR), but the underlying molecular mechanisms are incompletely understood. MicroRNAs (miRNAs) have been demonstrated to participate in the signalling pathways relevant to glucose metabolism in IR. The purpose of this study was to test whether the multiple-target anti-miRNA antisense oligonucleotides (MTg-AMO) technology, an innovative miRNA knockdown strategy, can be used to interfere with multiple miRNAs that play critical roles in regulating IR. Methods: An MTg-AMO carrying the antisense sequences targeting miR-106b, miR-27a and miR-30d was constructed (MTg-AMO106b/27a/30d). Protein levels were determined by Western blot analysis, and transcript levels were detected by real-time RT-PCR (qRT-PCR). Insulin resistance was analysed with glucose consumption and glucose uptake assays. Results: We found that the protein level of glucose transporter 4 (GLUT4), Mitogen-activated protein kinase 14 (MAPK 14), Phosphatidylinositol 3-kinase regulatory subunit beta (PI3K regulatory subunit beta) and mRNA level of Slc2a4 (encode GLUT4), Mapk14 (encode MAPK 14) and Pik3r2 (encode PI3K regulatory subunit beta) were all significantly down-regulated in the skeletal muscle of diabetic rats and in insulin-resistant L6 cells. Overexpression of miR-106b, miR-27a and miR-30d in L6 cells decreased glucose consumption and glucose uptake, and reduced the expression of GLUT4, MAPK 14 and PI3K regulatory subunit beta. Conversely, silencing of endogenous miR-106b, miR-27a and miR-30d in insulin-resistant L6 cells enhanced glucose consumption and glucose uptake, and increased the expression of GLUT4, MAPK 14 and PI3K regulatory subunit beta. MTg-AMO106b/27a/30d up-regulated the protein levels of GLUT4, MAPK 14 and PI3K regulatory subunit beta, enhanced glucose consumption and glucose uptake. Conclusion: Our data suggested that miR-106b, miR-27a and miR-30d play crucial roles in the regulation of glucose metabolism by targeting the GLUT4 signalling pathway in L6 cells. Moreover, MTg-AMO106b/27a/30d offers more potent effects than regular singular AMOs.
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Mair, Gillian E., Sven Reid Olson, and Joseph J. Shatzel. "The Safety of Novel Drugs Targeting Factor XI and XII in Human Clinical Trials:a Systematic Review." Blood 134, Supplement_1 (November 13, 2019): 4966. http://dx.doi.org/10.1182/blood-2019-130823.
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Introduction While effective at treating and preventing thrombosis, modern forms of anticoagulation universally increase the risk of hemorrhage. Data suggests that factors FXI and FXII could serve as druggable targets to provide anticoagulation without increasing the risk of bleeding. The purpose of this systematic review is to evaluate the safety of novel drugs targeting FXI and FXII in human clinical trials. Methods We performed a search in Ovid MEDLINE to identify published manuscripts describing administration of contact pathway-inhibiting drugs to humans. All human clinical trials evaluating a drug specific to FXI or FXII were included. Outcomes of interest collected for analysis included primarily bleeding events of any type, total adverse events (AEs)as well as other treatment-emergent adverse events (TEAE) and treatment-related adverse events (TRAE). Results A total of 338 published articles were identified from the original search. After screening, one phase 2 study of an antisense oligonucleotide (ISIS 416858) and three phase 1 trials of monoclonal antibodies (AB023, BAY1213790, MAA868) were included. A total of 465 patients across these 4 clinical trials were included. No patients experienced spontaneous bleeding. Postoperative bleeding occurred in 3% of patients treated with ISIS 416858 at each dose level and one patient experienced major bleeding. For comparison an 8% postoperative bleeding rate was seen in the arm treated with prophylactic low molecular weight heparin (LMWH). AB023, a monoclonal antibody inhibiting FXIIa-mediated activation of FXI to FXIa, was examined in a phase 1, dose-escalation trial in 21 healthy adults. Overall, there were no severe AEs. Minor AEs occurred in 10 of the 21 patients. 3 patients were deemed to possibly have TRAE. There was no statistical difference in bleeding time compared to placebo. activated thromboplastin time (aPTT) was prolonged for over a month after the highest dose level. BAY1213790 is a monoclonal antibody targeting the enzymatic active site of FXIa, and was studied in a phase 1 dose escalation trial in 83 healthy men. There were no severe AEs. Of the 54 subjects experiencing AEs, 34 were mild and 20 were moderate. TRAE were reported in 6 subjects. One subject had an infusion reaction and another subject requested the infusion be stopped. APTT showed a dose-dependent increase while bleeding times also did not increase compared to placebo. ISIS 416858 is an antisense oligonucleotide targeting FXI mRNA for degradation at its source within the hepatocyte. ISIS416858 was studied in a phase 2, randomized controlled trial in patients undergoing total knee arthroplasty. The safety and efficacy at preventing post-operative venous thromboembolism (VTE) was assessed at 200 mg or 300 mg doses compared to standard-of-care with LMWH. Bleeding occurred in 4 (3%), 2 (3%), and 6 (8%) patients in these three study groups, respectively. This was the only study drug where one patient experienced major bleeding. Mild AEs affected 219 subjects, with severe AEs occurring in 4 patients; only 2 discontinued ISIS416858. Patients in the 300 mg dose cohort of ISIS416858 experienced statistically fewer VTE events compared with LMWH; bleeding rates were numerically low compared to LMWH (3% vs 8%), though statistical significance was not reached. MAA868 is a monoclonal antibody targeting both the zymogen and active forms of FXI at the enzymatic active site, and was studied in a phase 1, dose-escalation clinical trial. MAA868 is unique due to its subcutaneous route of administration. Of the total 61 patient cohort, 34 patients experienced AEs and 9 TRAE. Only 2 severe, unrelated AEs occurred after the trial: one fatal cardiac arrest after elective surgery, and a gunshot wound requiring urgent surgery. MAA868 resulted in prolonged FXI suppression for up to four weeks. Conclusion Contact pathway-inhibiting drugs show promise as novel anticoagulation strategies that could significantly reduce the risk of bleeding seen with traditional anticoagulants. Additional studies are needed to further develop these drugs to test their efficacy at targeting the coagulation pathway in common settings of high risk for VTE, or existing thrombosis. The paradigm that anticoagulants cause bleeding could be broken in the near future based on this promising clinical data on contact pathway inhibition. Table Disclosures Shatzel: Aronora, Inc.: Consultancy.
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Patnaik, A., E. G. Chiorean, A. Tolcher, K. Papadopoulos, M. Beeram, D. Kee, M. Waddell, E. Gilles, and A. Buchbinder. "EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies." Journal of Clinical Oncology 27, no. 15_suppl (May 20, 2009): 2564. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.2564.
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2564 Background: HIF-1 is a transcription factor that regulates expression of many key genes, notably those switching cell metabolism to anaerobic glycolysis and inducing neovascularization in response to hypoxia. Increased HIF-1α levels are associated with poor prognosis in several neoplasms. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide suppressing HIF-1α mRNA translation in vitro (IC50 ∼1–5 nM). Methods: This study was designed to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2968. Pts with advanced malignancies were treated with EZN-2968 administered as a daily 2-hr IV infusion x 5 days every 4 weeks using a 3+3 dose-escalating design. Dose escalation was based on toxicities observed during Cycle 1. Results: 19 pts (11 men; median age = 60 y [47–79 y]) were treated with EZN-2968 doses of 0.5 (3 pts), 0.8 (3 pts), 1.2 (3 pts), 1.8 (4 pts), 2.7 (3 pts), and 4.1 (3 pts) mg/kg/day. Tumor types included colorectal cancer (7 pts); renal cancer (4 pts); soft-tissue sarcoma (STS; 2 pts); angiosarcoma (1 pt); melanoma (1 pt); and breast, ovarian, pancreatic, and prostate cancers (1 pt each). No dose-limiting toxicities were observed. The most common adverse events (Aes) were vomiting (32%); fatigue (26%); and anemia, diarrhea, nausea, and tumor pain (each 21%). Most Aes were Grade 1 or 2. Plasma PK for Day 1 is tabulated below. Stable disease was observed for 1 pt with angiosarcoma (28 wks) and 1 pt with renal cancer (12 wks). Conclusions: EZN-2968 was well tolerated in previously treated pts with advanced malignancies. PK data do not show accumulation of EZN-2968. Dose escalation is ongoing; final results will be presented at the meeting. Durable stable disease has been observed. [Table: see text] [Table: see text]
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Bianchini, Diletta, Aurelius Gabriel Omlin, Carmel Jo Pezaro, Deborah Mukherji, David Lorente Estelles, Andrea Zivi, Roberta Ferraldeschi, et al. "First-in-human phase I study of EZN-4176, a locked nucleic acid antisense oligonucleotide (LNA-ASO) to androgen receptor (AR) mRNA in patients with castration-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 5052. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5052.
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5052 Background: EZN-4176 is a third generationLNA-ASO that binds the ligand binding domain of AR mRNA resulting in full length AR mRNA degradation and decreased AR protein expression. Methods: Patients (pts) (performance status ECOG≤1) with progressing CRPC were eligible; prior abiraterone and enzalutamide treatment were allowed. EZN-4176 was administered as a weekly (QW) one-hour intravenous infusion. The starting dose was 0.5 mg/Kg with a 4-week dose-limiting toxicity (DLT) period. After determination of the DLT and the maximum tolerated dose (MTD) for weekly administration, a fortnightly schedule (Q2W) was initiated; a 3+3 modified Fibonacci dose escalation design was pursued. PD studies evaluated AR expression in tissue utilizing antibodies to the amino and carboxy-termini of the AR. Results: 22 pts were enrolled (median age 70.6 years, range 59 – 84 years). One pt was treated with the Q2W schedule. Two DLTs (G3/G4 ALT/AST elevation) occurred at 10 mg/Kg, which was therefore identified as the MTD for the weekly schedule. Multiple pts treated at 6.5 and 10 mg/Kg (5/9 pts, 55%) developed ≥G2 ALT and/or AST elevation after the first cycle requiring dose reduction and treatment delay. The most frequent adverse events (AEs) all-grades were fatigue (21/22 pts, 95.4%), nausea (10/22 pts, 45.4%), constipation (8/22 pts, 36.3%), AST (8/22 pts, 36.3%) and ALT (10/22 pts, 45.4%) elevation. The most frequent G3/4 AEs were AST (4/22 pts, 18.1%) and ALT (5/22 pts, 22.7%) elevation. Maximum PSA and circulating tumor cells (CTCs) declines are summarized below. There were no objective soft tissue responses. PD studies did not document any knockdown of AR expression Conclusions: EZN-4176 has limited antitumour activity in CRPC at its MTD for weekly administration. Safety, PK, PD and efficacy data will be presented. Clinical trial information: NCT01337518. [Table: see text]
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Alvarado, Y., H. Kantarjian, E. J. Freireich, G. Garcia-Manero, A. Ferrajoli, C. Koller, Z. Estrov, et al. "Phase II dosing study of cytarabine chemotherapy in combination with cenersen (EL625) and idarubicin in refractory and relapsed acute myelogenous leukemia (AML)." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7070. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7070.
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7070 Background: Cenersen is an antisense oligonucleotide that blocks production of p53. It sensitizes acute myeloid leukemia (AML) stem cells in vitro to DNA damage. Methods: Thirty-seven patients (13 refractory, 24 relapsed) with AML have been enrolled in the ongoing trial. All patients received cenersen (0.1 mg/kg/hr continuous intravenous infusion over 4 days [d]) plus Idarubicin (12mg/m2/dx3). Cytarabine was administered as follows: group (1) no cytarabine; (2) 100mg/m2/dx7; (3) 1g/m2/dx4 (3d > 60y). Chemotherapy started day 2. Results: Eighteen patients were treated per protocol and 19 were inevaluable to include 16 who received prohibited substances that block the action of cenersen (acetaminophen and/or high dose antioxidants). Six (33%) of those treated per protocol achieved CR compared to none of the 16 who received prohibited substances (p=0.02). This rate compares favorably to a literature report of a similar patient population (14%; Estey 1996). There were 2 patients who achieved a CRp, one of whom received acetaminophen on day 7. No significant differences in response occurred between the three treatment arms. The remission duration for 7 of the 8 responding patients was longer than the prior remission duration for the same patients. Several adverse events (AEs) (infection, bleeding, mucositis and hair loss) were significantly (p<0.001) less common for patients in this trial compared to the AE frequency described in the package insert for Idarubicin for its use in combination with standard dose Cytarabine. No adverse events attributable to cenersen were identified. Conclusions: We conclude that cenersen in combination with chemotherapy may improve the response rate compared to that expected with chemotherapy alone. No significant financial relationships to disclose.
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Artigas, F. "Joint Symposium: How Long Do We Have to Wait for the Antidepressant Effect? Mechanisms of Action for Delay of Onset Response to Antidepressants." European Psychiatry 41, S1 (April 2017): S3. http://dx.doi.org/10.1016/j.eurpsy.2017.01.017.
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Major depressive disorder (MDD) is a severe psychiatric syndrome with very high prevalence and socioeconomic impact. Monoamine-based antidepressant drugs (AD) display slow onset of action and limited efficacy. Preclinical studies show that ADs trigger a series of slow adaptive mechanisms that limit the clinical response. These mechanisms result from the pharmacological blockade of monoamine transporters (SERT, NET) and involve presynaptic, such as autoreceptor desensitization (e.g., 5-HT1A and 5-HT1B for serotonin neurons) as well as postsynaptic mechanisms, such as increased neurogenesis and expression of trophic factors, increased dendritic complexity, etc.Given the strong homeostasis of serotonin and noradrenaline neurons, a way to improve antidepressant action is to prevent self-inhibitory presynaptic mechanisms mediated by auto- and heteroreceptors after reuptake blockade. This strategy was used in the past with the non-selective 5-HT1A antagonist pindolol and has been incorporated by two recently developed AD (vilazodone and vortioxetine). Likewise, new molecular strategies using RNA interference (RNAi) show that the modulation of gene expression in serotonin neurons offers a great potential. Hence, local or intrnasal administration of small interfering RNA (siRNA) molecules targeting SERT or 5-HT1A autoreceptors evokes rapid and robust antidepressant-like effects in rodents.Moreover, glutamatergic drugs such as the non-competitive NMDA receptor antagonist ketmaine, offer a potential for the development of fast-acting AD due to its rapid and persistent antidepressant effects in treatment-resistant unipolar and bipolar patients after single i.v. infusion, an effect that likely involves the activation of AMPA receptors in ventral areas of the cingulate gyrus and the subsequent fast activation of serotonergic function.Disclosure of interestF.A. has received consulting honoraria on antidepressant drugs from Lundbeck and he has been PI of grants from Lundbeck. He is also co-author of the patent WO/2011/131693 for the siRNA and ASO (antisense oligonucleotides) molecules.
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Ko, Andrew H., Patrick B. Murphy, James D. Peyton, Dianna Shipley, Ahmed Al-Hazzouri, Frank A. Rodriguez, Mark S. Womack, et al. "RAINIER: A randomized, double-blinded, placebo-controlled phase II trial of gemcitabine (gem) plus nab-paclitaxel (nab-P) combined with apatorsen (A) or placebo (Pl) in patients (pts) with metastatic pancreatic cancer (mPC)." Journal of Clinical Oncology 34, no. 4_suppl (February 1, 2016): 419. http://dx.doi.org/10.1200/jco.2016.34.4_suppl.419.
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419 Background: Heat shock protein 27 (Hsp27) is over-expressed in PC, enabling tumor growth and metastasis. A is an antisense oligonucleotide that binds to Hsp27 mRNA and inhibits production of Hsp27 protein. This randomized phase II trial evaluates the efficacy of gem/nab-P plus A or Pl in pts with mPC. Methods: Pts with untreated mPC were randomized 1:1 to Arm A (gem, nab-P, A) or Arm B (gem, nab-P, Pl). 3 loading doses of 600mg A IV or Pl IV were given, then 600 mg A or Pl weekly with chemotherapy in 28 day cycles. Both arms received gem 1000mg/m2 IV, nab-P 125mg/m2 IV days 1, 8, and 15. Restaging was every 2 cycles. Serum Hsp27 levels were collected at baseline and on treatment. Primary endpoint compared overall survival (OS); secondary endpoints were progression free survival (PFS), response rate (RR), CA 19-9 response, and toxicity. Results: 132 pts were randomized: median age 66 yrs, 57% male, 47% ECOG 0. Demographics were similar for both arms. 36% of pts on Arm A and 48% of pts Arm B discontinued due to progressive disease, and 24% and 14% due to adverse events (AEs). There was a higher incidence of ≥Grade (G) 4 and serious adverse events (SAEs) in Arm A. The most frequently reported G 3/4 treatment-related AEs were anemia (20%), neutropenia (17%), and fatigue (16%) on Arm A and anemia (27%), neutropenia (19%), and thrombocytopenia (13%) on Arm B. Overall RR was 18% on each arm. With a median f/u of 9.1 mos, median PFS and OS are 2.7 and 5.2 mos on Arm A and 3.8 and 6.9 mos on Arm B (p=NS). Correlative analyses between Hsp27 expression and clinical outcomes will be presented. In a statistical model using only Arm B data, 3 base attributes, ECOG >0, liver mets, and neutrophil levels had a strong prognostic relationship to OS. Conclusions: This study showed no improvement in clinical outcomes adding A to gem plus nab-p. G 4 AEs and SAEs were increased with A. We await analysis for Hsp 27 and CA 19-9 levels and further analysis to identify any pt subgroup who might have benefited from the experimental treatment. Clinical trial information: NCT01844817.
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Wiechno, Pawel J., Piotr Chlosta, Joanna Pikiel, Bradley G. Somer, Begoña Mellado, Ignacio Duran Martinez, Daniel E. Castellano, et al. "Randomized phase II study with window-design to evaluate anti-tumor activity of the survivin antisense oligonucleotide (ASO) ly2181308 in combination with docetaxel for first-line treatment of castrate-resistant prostate cancer (CRPC)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 5019. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.5019.
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5019 Background: In prostate cancer, expression of survivin, a protein that inhibits apoptosis, is associated with resistance to taxanes and poor outcome. LY2181308 reduces survivin expression and consequently is expected to improve activity of taxanes, such as docetaxel. A randomized phase II study was conducted to assess the activity of the combination. Methods: Adult patients (pts) with CRPC, ECOG performance status <2, and no bone or CNSmetastases were randomized 1:2 to standard docetaxel/prednisone every 21 days (Arm A) or standard therapy combined with LY2181308 given as a 3-hr IV infusion (Arm B). Analysis was planned and performed after 130 pts progressed or died. This assessment provided a 70% chance of detecting a difference in progression-free survival (PFS) at the 10% significance level. Initially, LY2181308 was given as a loading dose (3 consecutive days) and then as a weekly 3-hr IV maintenance dose. Arm B also included a window treatment with LY2181308 monotherapy equivalent to a 21-day cycle of docetaxel before starting combined treatment. The primary endpoint was PFS. Results: This study enrolled 154 pts. The median PFS for Arm B was 8.64 (90% CI, 7.39–10.45) months vs. 9.00 (90% CI, 7.00–10.09) months in Arm A, showing no statistical difference (log rank p=0.755). The median overall survival (OS) for Arm B was 27.04 (90% CI, 19.94–33.41) months vs. 29.04 (90% CI, 20.11–39.26) months for Arm A (log-rank p= 0.838). The PSA responses (>50% reduction in PSA) were similar: 56.9% for Arm A and 56.1% in Arm B (p=0.856). Most pts had no pain or mild pain at baseline and during the active period. Pts treated in Arm B had a higher frequency of serious and nonserious adverse events (AEs) than those in Arm A. The observed AE and pharmacokinetic (PK) profiles were consistent with the known safety and PK profiles of LY2181308 and docetaxel. Conclusions: The addition of LY2181308 to a standard docetaxel/prednisone regimen showed no improvement in PFS, PSA response, and OS in first line CRPC pts. The safety profile of docetaxel and LY2181308 is predictable and consistent with the known safety profiles. Clinical trial information: NCT00642018.
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Liu, Que, Claudette Bethune, Esmat Dessouki, John Grundy, Brett P. Monia, and Sanjay Bhanot. "ISIS-FXIRx, A Novel and Specific Antisense Inhibitor of Factor XI, Caused Significant Reduction in FXI Antigen and Activity and Increased aPTT without Causing Bleeding in Healthy Volunteers." Blood 118, no. 21 (November 18, 2011): 209. http://dx.doi.org/10.1182/blood.v118.21.209.209.
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Abstract Abstract 209 Background: Factor XI (FXI) deficient subjects (Hemophilia C) have a low incidence of stroke and venous thromboembolism and yet do not exhibit spontaneous bleeding events, suggesting that inhibition of FXI activity (FXI:C) may be an attractive antithrombotic therapeutic strategy. We have previously demonstrated that treatment with FXI antisense oligonucleotides results in robust antithrombotic effects in multiple models of venous and arterial thrombosis without causing bleeding, validating this therapeutic approach preclinically. Objectives: To investigate the safety, tolerability, pharmacokinetics and pharmacodynamics (FXI antigen, FXI:C and aPTT) of single and multiple doses of ISIS-FXIRx or placebo in healthy volunteers. Methods: In this double blind, single or multiple ascending-dose (SAD or MAD) study, healthy subjects aged 18 to 65 years were randomly assigned in a 3:1 ratio to receive ISIS- FXIRx or placebo (normal saline) administered as a single subcutaneous (SC) injection at 50, 100, 200 and 300 mg/kg (n=8/cohort, except 200 mg cohort n=16), or as multiple SC injections (n=12/cohort). In the MAD cohorts, subjects received 8 SC doses over 6-weeks (3 doses in Week 1 followed by once weekly dosing for 5 weeks). Results: In the SAD cohorts, both FXI antigen and FXI:C in the 200 and 300 mg cohorts were significantly reduced 1-week after dosing. In the MAD cohorts (interim analysis, data for 300 mg not analyzed to date), treatment with ISIS- FXIRx demonstrated a robust, sustained and dose-dependent reduction in FXI antigen and FXI:C as compared with placebo group, with maximum reduction observed 1–2 weeks post-dosing (Table). These reductions were accompanied by a concomitant increase in aPTT. Mean (%) Change From Baseline in the MAD Cohorts Furthermore, in the 200 mg multiple cohort, FXI:C and FXI antigen were reduced by 92% and 100% respectively in one subject after 6 weeks dosing with no symptoms, including bleeding. Significant correlation between FXI:C reduction and aPTT prolongation was observed (r=-0.8123, p=0.0078). No study drug related bleeding events were reported. ISIS-FXIRx did not cause clinically significant changes in vital signs, ECG, hepatic function, renal function or hematology. One serious AE (allergic reaction) was reported in the 200 mg single dose cohort in an ISIS-FXIRx treated subject, who recovered completely. Most AEs were mild. SC injections of ISIS-FXIRx were well tolerated with mild injection site reactions reported in 33% of the subjects vs. 10.5% in placebo group. Preliminary PK analysis indicates hepatic T1/2 of ISIS-FXIRx across doses to be ∼20 days. Conclusions: Treatment with ISIS- FXIRx in healthy volunteers demonstrated a statistically significant and sustained reduction of FXI:C, FXI antigen and prolonged aPTT with an acceptable safety and tolerability profile. No bleeding events related to ISIS- FXIRx were found. These data provide further support for development of ISIS-FXIRx as a novel approach for the treatment and prevention of thromboembolic disorders. Disclosures: Liu: ISIS Pharmaceuticals: Employment. Bethune:ISIS Pharmaceuticals: Employment. Dessouki:ISIS Pharmaceuticals: Consultancy. Grundy:ISIS Pharmaceuticals: Employment. Monia:Isis Pharmaceuticals: Employment. Bhanot:ISIS Pharmaceuticals: Employment.
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Brannagan, Thomas, Annabel K. Wang, Teresa Coelho, Marcia Waddington Cruz, Michael J. Polydefkis, Peter J. Dyck, Violaine Plante-Bordeneuve, et al. "Long-Term Update from the Open-Label Extension of the NEURO-TTR Study in Patients with Hereditary Transthyretin Amyloidosis." Blood 132, Supplement 1 (November 29, 2018): 498. http://dx.doi.org/10.1182/blood-2018-99-116995.
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Abstract Background: Hereditary transthyretin amyloidosis (hATTR) is a rare, progressive, and fatal disease caused by the buildup of transthyretin-derived amyloid protein in major organs, predominantly affecting the peripheral nerves and heart. Inotersen, a second-generation antisense oligonucleotide targeting TTR mRNA, has shown efficacy and safety in patients with hATTR in a randomized, double-blind, placebo-controlled, phase 3 study, NEURO-TTR (ClinicalTrials.gov, NCT01737398; Benson NEJM 2018). Patients with hATTR amyloidosis who completed the NEURO-TTR study were eligible to receive inotersen for up to 5 years in a phase 3 open-label extension study (ClinicalTrials.gov, NCT02175004). Methods: In NEURO-TTR, patients were randomized 2:1 to receive inotersen (300-mg weekly subcutaneous doses) or placebo. In the open-label extension, patients continued inotersen (inotersen-inotersen) or switched from placebo to inotersen (placebo-inotersen). Evaluations included modified Neuropathy Impairment Score +7 neurophysiologic tests composite score (mNIS+7; higher scores indicate worse neuropathy), Norfolk Quality of Life-Diabetic Neuropathy questionnaire total score (Norfolk QoL-DN; higher scores indicate worse QoL), and adverse events (AEs). Cardiomyopathy (CM) was defined by a diagnosis of hATTR-CM at trial entry or by an interventricular wall thickness of 13 mm or more on transthoracic echocardiography at baseline, as ascertained by a central reader, or no known history of persistent hypertension (systolic blood pressure, ≥150 mm Hg) within 12 months before screening. Results : In the placebo-controlled, double-blind, phase 3 NEURO-TTR study, 112/172 patients were randomized and received inotersen. At baseline, patients were predominantly white (91.9%) males (68.6%) with a mean age of 59.2 years. A total of 67.4% had stage I (ambulatory) and 32.6% had stage II (ambulatory with assistance) disease. Inotersen-treated patients who had stage II disease had a longer duration of disease from diagnosis (40.9 vs 24.8 months, respectively) and from onset (72.6 vs 63.2 months, respectively) of hATTR polyneuropathy symptoms compared with placebo-treated patients who had stage II disease, indicating more advanced disease. A higher proportion of inotersen-treated patients had CM at baseline (67% vs 55%, respectively), and more severe CM, measured by higher NT-proBNP levels and longer duration of disease from hATTR-CM symptom onset, compared with placebo-treated patients. In the phase 3 open-label extension study as of Sept 15, 2017, 134 of 135 patients enrolled received ≥1 dose of inotersen. The mean age was 60.4 years and most patients were male (69.4%). Extended dosing with inotersen up to 27 months continued to improve mNIS+7 and Norfolk QoL-DN in the open-label extension compared to placebo-treated patients at week 66 in the double-blind NEURO-TTR study; mean changes from open-label extension baseline to open-label extension week 52 in the inotersen-inotersen group were 5.1 points for mNIS+7 (vs 25.5 for placebo-treated patients in the double-blind NEURO-TTR study) and 3.9 points for Norfolk QoL-DN (vs 10.7 for placebo-treated patients in the double-blind NEURO-TTR study). Initiation of inotersen in placebo-treated patients (placebo-inotersen) resulted in improvement in mNIS+7 and Norfolk QoL-DN by week 26. Few patients discontinued treatment because of AEs (inotersen-inotersen, 9%; placebo-inotersen, 4%). The rate of treatment-related serious AEs was low in both treatment groups (2% each). There was no evidence of increased risk for grade 4 thrombocytopenia or severe renal events with increased duration of exposure. We will present 2-year follow-up results from the open-label extension study. Conclusions: Results of the open-label extension show continued benefit, measured by mNIS+7 and Norfolk QoL-DN, and confirmed that earlier initiation of treatment is important for optimal clinical outcomes. No new safety concerns were identified. Results from the longer-term follow-up for the open-label extension will further elucidate how inotersen may benefit patients with hATTR amyloidosis. Disclosures Brannagan: Alnylam: Honoraria, Other: Investigator, Speakers Bureau; Ionis: Other: Investigator. Wang:Ionis: Other: Investigator, Speakers Bureau. Coelho:Prothena: Consultancy, Honoraria; Ionis: Consultancy, Other: Investigator; Alnylam: Consultancy, Honoraria, Other: Investigator; Pfizer: Consultancy, Honoraria, Other: Investigator. Waddington Cruz:Ionis: Honoraria; Genzyme/Sanofi: Honoraria; Pfizer: Honoraria. Polydefkis:Pfizer: Honoraria; Alnylam: Honoraria. Dyck:Ionis: Consultancy; Alnylam: Consultancy. Plante-Bordeneuve:Alnylam: Consultancy; Pfizer: Consultancy, Other: reimbursement for travel and meeting; Ionis: Other: reimbursement for travel and meeting. Berk:Ionis: Honoraria, Other: Investigator; Alnylam: Honoraria, Other: Investigator; Pfizer: Other: Investigator. Barroso:Pfizer: Consultancy, Honoraria, Other: Thaos registry, Speakers Bureau; Alnylam: Honoraria, Other: Investigator. Conceição:Alnylam: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Sanofi: Honoraria, Speakers Bureau. Hughes:Ionis: Employment. Kwoh:Ionis: Employment. Jung:Ionis: Employment. Guthrie:Akcea: Employment. Pollock:Akcea: Employment. Benson:Ionis: Other: Investigator, Research Funding. Gertz:janssen: Consultancy; Teva: Consultancy; spectrum: Consultancy, Honoraria; Alnylam: Honoraria; Ionis: Honoraria; Amgen: Consultancy; annexon: Consultancy; Prothena: Honoraria; Research to Practice: Consultancy; Apellis: Consultancy; celgene: Consultancy; Abbvie: Consultancy; Medscape: Consultancy; Physicians Education Resource: Consultancy.
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Ham, Kristin A., Niall P. Keegan, Craig S. McIntosh, May T. Aung-Htut, Khine Zaw, Kane Greer, Sue Fletcher, and Steve D. Wilton. "Induction of cryptic pre-mRNA splice-switching by antisense oligonucleotides." Scientific Reports 11, no. 1 (July 23, 2021). http://dx.doi.org/10.1038/s41598-021-94639-x.
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AbstractAntisense oligomers (AOs) are increasingly being used to modulate RNA splicing in live cells, both for research and for the development of therapeutics. While the most common intended effect of these AOs is to induce skipping of whole exons, rare examples are emerging of AOs that induce skipping of only part of an exon, through activation of an internal cryptic splice site. In this report, we examined seven AO-induced cryptic splice sites in six genes. Five of these cryptic splice sites were discovered through our own experiments, and two originated from other published reports. We modelled the predicted effects of AO binding on the secondary structure of each of the RNA targets, and how these alterations would in turn affect the accessibility of the RNA to splice factors. We observed that a common predicted effect of AO binding was disruption of the exon definition signal within the exon’s excluded segment.
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Holliday, Mira, Emma S. Singer, Samantha B. Ross, Seakcheng Lim, Sean Lal, Jodie Ingles, Christopher Semsarian, and Richard D. Bagnall. "Transcriptome Sequencing of Patients With Hypertrophic Cardiomyopathy Reveals Novel Splice-Altering Variants in MYBPC3." Circulation: Genomic and Precision Medicine 14, no. 2 (April 2021). http://dx.doi.org/10.1161/circgen.120.003202.
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Background: Transcriptome sequencing can improve genetic diagnosis of Mendelian diseases but requires access to tissue expressing disease-relevant transcripts. We explored genetic testing of hypertrophic cardiomyopathy using transcriptome sequencing of patient-specific human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs). We also explored whether antisense oligonucleotides (AOs) could inhibit aberrant mRNA splicing in hiPSC-CMs. Methods: We derived hiPSC-CMs from patients with hypertrophic cardiomyopathy due to MYBPC3 splice-gain variants, or an unresolved genetic cause. We used transcriptome sequencing of hiPSC-CM RNA to identify pathogenic splicing and used AOs to inhibit this splicing. Results: Transcriptome sequencing of hiPSC-CMs confirmed aberrant splicing in 2 people with previously identified MYBPC3 splice-gain variants (c.1090+453C>T and c.1224-52G>A). In a patient with an unresolved genetic cause of hypertrophic cardiomyopathy following genome sequencing, transcriptome sequencing of hiPSC-CMs revealed diverse cryptic exon splicing due to an MYBPC3 c.1928-569G>T variant, and this was confirmed in cardiac tissue from an affected sibling. Antisense oligonucleotide treatment demonstrated almost complete inhibition of cryptic exon splicing in one patient-specific hiPSC-CM line. Conclusions: Transcriptome sequencing of patient specific hiPSC-CMs solved a previously undiagnosed genetic cause of hypertrophic cardiomyopathy and may be a useful adjunct approach to genetic testing. Antisense oligonucleotide inhibition of cryptic exon splicing is a potential future personalized therapeutic option.
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Ugovšek, Sabina, Janja Zupan, Andreja Rehberger Likozar, and Miran Sebestjen. "Influence of lipid-lowering drugs on inflammation: what is yet to be done?" Archives of Medical Science, March 20, 2021. http://dx.doi.org/10.5114/aoms/133936.
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Atherosclerosis is a chronic inflammatory disease that is associated with risk of cardiovascular events. The best-characterised and well-standardised clinical indicator of inflammation is C-reactive protein. Current evidence-based drug therapies for prevention and treatment of cardiovascular diseases are mainly focused on reduction of low-density lipoprotein cholesterol. However, these drugs do not provide sufficient protection against recurrent cardiovascular events. One of the possible mechanisms behind this recurrence might be the persistence of residual inflammation. For the most commonly used lipid-lowering drugs, the statins, their reduction of cardiovascular events goes beyond lowering of low-density lipoprotein cholesterol. Here, we review the effects of these lipid-lowering drugs on inflammation, in terms of statins, ezetimibe, fibrates, niacin, proprotein convertase subtilisin/kexin type 9 inhibitors, bempedoic acid, ethyl eicosapentaenoic acid and antisense oligonucleotides. We focus in particular on C-reactive protein, and discuss how the effects of the statins might be related to reduced rates of cardiovascular events.
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Okumura, Sho, Yu Hirano, and Yasuo Komatsu. "Stable duplex-linked antisense targeting miR-148a inhibits breast cancer cell proliferation." Scientific Reports 11, no. 1 (June 1, 2021). http://dx.doi.org/10.1038/s41598-021-90972-3.
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AbstractMicroRNAs (miRNAs) regulate cancer cell proliferation by binding directly to the untranslated regions of messenger RNA (mRNA). MicroRNA-148a (miR-148a) is expressed at low levels in breast cancer (BC). However, little attention has been paid to the sequestration of miR-148a. Here, we performed a knockdown of miR-148a using anti-miRNA oligonucleotides (AMOs) and investigated the effect on BC cell proliferation. BC cell proliferation was significantly suppressed by AMO flanked by interstrand cross-linked duplexes (CL-AMO), whereas single-stranded and commercially available AMOs had no effect. The suppression was caused by sequestering specifically miR-148a. Indeed, miR-148b, another member of the miR-148 family, was not affected. Importantly, the downregulation of miR-148a induced a greater and longer-lasting inhibition of BC cell proliferation than the targeting of oncogenic microRNA-21 (miR-21) did. We identified thioredoxin-interacting protein (TXNIP), a tumor suppressor gene, as a target of miR-148a and showed that CL-AMO provoked an increase in TXNIP mRNA expression. This study provide evidence that lowly expressed miRNAs such as miR-148a have an oncogenic function and might be a promising target for cancer treatment.
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Mix, Lucas, Benedikt Winter, Claudia D. Wurster, Sophia Platen, Simon Witzel, Zeljko Uzelac, Heiko Graf, Albert C. Ludolph, and Dorothée Lulé. "Quality of Life in SMA Patients Under Treatment With Nusinersen." Frontiers in Neurology 12 (March 29, 2021). http://dx.doi.org/10.3389/fneur.2021.626787.
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Background: Spinal Muscular Atrophy (SMA) is a severe neurodegenerative disease, characterized by progressive muscle weakness and atrophy. The approval of the antisense oligonucleotide (ASO) nusinersen now provides an effective pharmacological approach with the potential to slow down or stop disease progression with a potentially major impact on patients' well-being.Objective: This study evaluates quality of life (QoL) in pediatric and adult patients over the course of therapy with nusinersen.Methods: Twenty-six SMA patients treated with nusinersen were evaluated regarding global QoL (gQoL), health-related QoL (HRQoL) and depressiveness. Assessments were conducted three times over the first 6 months of treatment. Applied were different questionnaires: the Anamnestic Comparative Self-Assessment (ACSA) for gQoL, the Short Form-36 Health Survey (SF-36) for HRQoL in adult patients and the ALS Depression Inventory 12 Items (ADI-12) for depressiveness. The sample was matched with 22 healthy controls.Results: Despite severe physical restrictions, patients reported high levels of QoL and low levels of depressiveness at study entry. Early disease onset and low levels of physical functioning were associated with better gQoL and lower levels of depressiveness. A significant decrease of gQoL in patients was evident over the course of the study. Still, adult patients reported a significant increase in perceived health.Conclusions: Our study provides first insight that SMA patients experience a gQoL superior to healthy controls at start of therapy. This might indicate patients' high hopes and expectations toward treatment. gQoL returns to a level similar to that of healthy controls over the course of therapy.
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Duan, Fu-Gang, Mei-Fang Wang, Ya-Bing Cao, Dan Li, Run-Ze Li, Xing-Xing Fan, Imran Khan, et al. "MicroRNA-421 confers paclitaxel resistance by binding to the KEAP1 3′UTR and predicts poor survival in non-small cell lung cancer." Cell Death & Disease 10, no. 11 (October 28, 2019). http://dx.doi.org/10.1038/s41419-019-2031-1.
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Abstract MicroRNAs regulate post-transcriptional gene expression and play important roles in multiple cellular processes. In this study, we found that miR-421 suppresses kelch-like ECH-associated protein 1(KEAP1) expression by targeting its 3′-untranslated region (3′UTR). A Q-PCR assay demonstrated that miR-421 is overexpressed in non-small cell lung cancer (NSCLC), especially in A549 cells. Consistently, the level of miR-421 was higher in clinical blood samples from lung cancer patients than in those from normal healthy donors, suggesting that miR-421 is an important lung cancer biomarker. Interestingly, overexpression of miR-421 reduced the level of KEAP1 expression, which further promoted lung cancer cell migration and invasion, as well as inhibited cell apoptosis both in vivo and in vitro. Furthermore, knockdown of miR-421 expression with an antisense morpholino oligonucleotide (AMO) increased ROS levels and treatment sensitivity to paclitaxel in vitro and in vivo, indicating that high miR-421 expression may at least partly account for paclitaxel tolerance in lung cancer patients. To find the upstream regulator of miR-421, one of the candidates, β-catenin, was knocked out via the CRISPR/Cas9 method in A549 cells. Our data showed that inhibiting β-catenin reduced miR-421 levels in A549 cells. In addition, β-catenin upregulation enhanced miR-421 expression, indicating that β-catenin regulates the expression of miR-421 in lung cancer. Taken together, our findings reveal the critical role of miR-421 in paclitaxel drug resistance and its upstream and downstream regulatory mechanisms. Therefore, miR-421 may serve as a potential molecular therapeutic target in lung cancer, and AMOs may be a potential treatment strategy.
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Landmesser, Ulf, Arash Haghikia, Lawrence A. Leiter, R. Scott Wright, David Kallend, Peter Wijngaard, Robert Stoekenbroek, John Jp Kastelein, and Kausik K. Ray. "Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1." Cardiovascular Research, April 4, 2020. http://dx.doi.org/10.1093/cvr/cvaa077.
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Abstract Aims Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. Methods and results The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: −0.5%; 500 mg: −1.8%; DD: 100 mg: 1.3%; 200 mg: −0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. Conclusion In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
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Chen, Yu, Sirirat Surinkaew, Jiening Xiao, Chia T. Wu, Hai Huang, Yiguo Sun, Dobromir Dobrev, and Stanley Nattel. "Abstract 12229: MicroRNA Regulation of JAK-STAT System in the Atrial Fibrillation-Related Fibrotic Response." Circulation 132, suppl_3 (November 10, 2015). http://dx.doi.org/10.1161/circ.132.suppl_3.12229.
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Introduction: MicroRNAs (miRNAs) are involved in cardiac remodeling, but their role in atrial fibrillation (AF) is poorly understood. JAK-STAT signalling is activated by the pro-fibrotic mediator PDGF, but its contribution to AF substrate formation is unknown. Here, we investigated miRNA regulation of the JAK-STAT system in in the heart failure (HF) induced AF fibrotic substrate. Methods: HF was induced in dogs by ventricular tachypacing (VTP, 240 bpm) for 2 weeks. Fibroblasts (FBs) isolated from the left atrium (LA) and left ventricle (LV) of control (CTL) dogs were treated with PDGF-AB. PDGF, JAK2, STAT3 and miRNA expression was assessed by qPCR. JAK2, STAT3 and collagen-I (COL-1) proteins were quantified by Western Blot. miRNA targets were validated by luciferase reporter assay. miRNA mimic or antisense oligonucleotides (AMOs) were used for miRNA manipulation in FBs. Results: HF dogs developed AF susceptibility and LA-selective fibrosis beginning at 1 wk VTP. PDGF and JAK2 mRNA, along with phosphorylated (activated) JAK2 protein, were increased in HF atria (by 1.4-2.9* fold, *p<0.05). miR-30a and miR-133a were predicted bioinformatically to target JAK2, and were downregulated by 51%-52%** and 48%-71%** (**p<0.01) in HF LA FBs at 1-2 wk VTP. PDGF-AB increased the expression of JAK2 and STAT3 mRNA (by 1.4-1.5* fold) and COL-1 protein (by 2*** fold, ***p<0.001) in canine LA FBs, while reducing the expression of miR-30a and miR-133a (by ~50%-80% ***). Smaller changes were seen in LV FBs with PDGF-stimulation. Luciferase assay confirmed miR-30a and miR-133a targeting of JAK2. Overexpression of miR-133a downregulated JAK2 mRNA (by 30%***) and protein (by 50%, p=0.05) in LA FBs. This effect was abolished by co-transfection of miR-133a and AMO-133a. The upregulation of JAK2 and COL-1 expression induced by PDGF-AB stimulation was reversed by miR-133a overexpression in LA FBs (reduced by 49%* and 53%*** versus PDGF stimulation alone). Conclusions: PDGF-induced disinhibition of JAK2 expression by downregulation of miR-30a and miR-133a may contribute to AF-associated fibrotic responses. MicroRNA targeting of the JAK-STAT system regulates LA FB function, appears to be involved in HF-induced LA fibrosis and is a potential therapeutic target for AF prevention.