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Antisense oligonucleotide

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https://www.readbyqxmd.com/read/29052441/investigational-glucagon-receptor-antagonists-in-phase-i-and-ii-clinical-trials-for-diabetes
#1
André J Scheen, Nicolas Paquot, Pierre J Lefèbvre
Despite type 2 diabetes (T2D) being recognized as a bihormonal pancreatic disease, current therapies are mainly focusing on insulin, while targeting glucagon has been long dismissed. However, glucagon receptor (GCGr) antagonists are currently investigated in clinical trials. Area covered: Following a brief description of the rationale for antagonizing GCGr in T2D, lessons from GCGr knock-out mice and pharmacological means to antagonize GCGr, a detailed description of the main results obtained with GCGr antagonists in Phase I-II clinical trials is provided...
October 20, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/29038471/myoblasts-and-macrophages-are-required-for-therapeutic-morpholino-antisense-oligonucleotide-delivery-to-dystrophic-muscle
#2
James S Novak, Marshall W Hogarth, Jessica F Boehler, Marie Nearing, Maria C Vila, Raul Heredia, Alyson A Fiorillo, Aiping Zhang, Yetrib Hathout, Eric P Hoffman, Jyoti K Jaiswal, Kanneboyina Nagaraju, Sebahattin Cirak, Terence A Partridge
Exon skipping is a promising therapeutic strategy for Duchenne muscular dystrophy (DMD), employing morpholino antisense oligonucleotides (PMO-AO) to exclude disruptive exons from the mutant DMD transcript and elicit production of truncated dystrophin protein. Clinical trials for PMO show variable and sporadic dystrophin rescue. Here, we show that robust PMO uptake and efficient production of dystrophin following PMO administration coincide with areas of myofiber regeneration and inflammation. PMO localization is sustained in inflammatory foci where it enters macrophages, actively differentiating myoblasts and newly forming myotubes...
October 16, 2017: Nature Communications
https://www.readbyqxmd.com/read/29037933/role-of-maternal-xenopus-syntabulin-in-germ-plasm-aggregation-and-primordial-germ-cell-specification
#3
Denise Oh, Douglas W Houston
The localization and organization of mitochondria- and ribonucleoprotein granule-rich germ plasm is essential for many aspects of germ cell development. In Xenopus, germ plasm is maternally inherited and is required for the specification of primordial germ cells (PGCs). Germ plasm is aggregated into larger patches during egg activation and cleavage and is ultimately translocated perinuclearly during gastrulation. Although microtubule dynamics and a kinesin (Kif4a) have been implicated in Xenopus germ plasm localization, little is known about how germ plasm distribution is regulated...
October 13, 2017: Developmental Biology
https://www.readbyqxmd.com/read/29037661/antisense-oligonucleotide-therapy-rescues-disruptions-in-organization-of-exploratory-movements-associated-with-usher-syndrome-type-1c-in-mice
#4
Tia N Donaldson, Kelsey T Jennings, Lucia A Cherep, Adam M McNeela, Frederic F Depreux, Francine M Jodelka, Michelle L Hastings, Douglas G Wallace
Usher syndrome, Type 1C (USH1C) is an autosomal recessive inherited disorder in which a mutation in the gene encoding harmonin is associated with multi-sensory deficits (i.e., auditory, vestibular, and visual). USH1C (Usher) mice, engineered with a human USH1C mutation, exhibit these multi-sensory deficits by circling behavior and lack of response to sound. Administration of an antisense oligonucleotide (ASO) therapeutic that corrects expression of the mutated USH1C gene, has been shown to increase harmonin levels, reduce circling behavior, and improve vestibular and auditory function...
October 13, 2017: Behavioural Brain Research
https://www.readbyqxmd.com/read/29035327/immortalized-muscle-cell-model-to-test-the-exon-skipping-efficacy-for-duchenne-muscular-dystrophy
#5
REVIEW
Quynh Nguyen, Toshifumi Yokota
Duchenne muscular dystrophy (DMD) is a lethal genetic disorder that most commonly results from mutations disrupting the reading frame of the dystrophin (DMD) gene. Among the therapeutic approaches employed, exon skipping using antisense oligonucleotides (AOs) is one of the most promising strategies. This strategy aims to restore the reading frame, thus producing a truncated, yet functioning dystrophin protein. In 2016, the Food and Drug Administration (FDA) conditionally approved the first AO-based drug, eteplirsen (Exondys 51), developed for DMD exon 51 skipping...
October 16, 2017: Journal of Personalized Medicine
https://www.readbyqxmd.com/read/29034834/challenges-and-advances-in-gene-therapy-approaches-for-neurodegenerative-disorders
#6
Aneesh Donde, Philip C Wong, Liam L Chen
INTRODUCTION: The recent approval of Spinraza (nusinersen), an antisense oligonucleotide, by U.S. Food and Drug Administration to treat patients with spinal muscular atrophy, has reignited interests of researchers in designing and testing new gene therapy approaches to treat neurological disorders, in particular, to curb neurodegenerative diseases of the central nervous system which represent an everincreasing public health burden to today's society. CONCLUSION: This review highlights several key factors to be taken into consideration to design successful preclinical and clinical gene therapy experiments with respect to the vehicle of delivery and the route of administration to CNS-specific targets, with an additional focus on antisense oligonucleotide therapy and recent clinical trial developments...
October 13, 2017: Current Gene Therapy
https://www.readbyqxmd.com/read/29033099/custirsen-ogx-011-combined-with-cabazitaxel-and-prednisone-versus-cabazitaxel-and-prednisone-alone-in-patients-with-metastatic-castration-resistant-prostate-cancer-previously-treated-with-docetaxel-affinity-a-randomised-open-label-international-phase-3-trial
#7
Tomasz M Beer, Sebastien J Hotte, Fred Saad, Boris Alekseev, Vsevolod Matveev, Aude Fléchon, Gwenaelle Gravis, Florence Joly, Kim N Chi, Zafar Malik, Brent Blumenstein, Patricia S Stewart, Cindy A Jacobs, Karim Fizazi
BACKGROUND: Docetaxel and cabazitaxel improve overall survival compared with mitoxantrone in patients with metastatic castration-resistant prostate cancer. Custirsen (OGX011) is a second generation highly specific antisense oligonucleotide that inhibits the production of clusterin, an antiapoptotic protein that is upregulated in response to chemotherapy and that confers treatment resistance. We aimed to assess whether custirsen in combination with cabazitaxel and prednisone increases overall survival in patients with metastatic castration-resistant prostate cancer previously treated with docetaxel...
October 9, 2017: Lancet Oncology
https://www.readbyqxmd.com/read/29027965/enhancing-the-therapeutic-delivery-of-oligonucleotides-by-chemical-modification-and-nanoparticle-encapsulation
#8
REVIEW
Yating Sun, Yarong Zhao, Xiuting Zhao, Robert J Lee, Lesheng Teng, Chenguang Zhou
Oligonucleotide (ON) drugs, including small interfering RNA (siRNA), microRNA (miRNA) and antisense oligonucleotides, are promising therapeutic agents. However, their low membrane permeability and sensitivity to nucleases present challenges to in vivo delivery. Chemical modifications of the ON offer a potential solution to improve the stability and efficacy of ON drugs. Combined with nanoparticle encapsulation, delivery at the site of action and gene silencing activity of chemically modified ON drugs can be further enhanced...
October 13, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29027668/decreased-sorbitol-synthesis-leads-to-abnormal-stamen-development-and-reduced-pollen-tube-growth-via-an-myb-transcription-factor-mdmyb39l-in-apple-malus-domestica
#9
Dong Meng, Mingyang He, Yang Bai, Hongxia Xu, Abhaya M Dandekar, Zhangjun Fei, Lailiang Cheng
Sugars produced by photosynthesis not only fuel plant growth and development, but may also act as signals to regulate plant growth and development. This work focuses on the role of sorbitol, a sugar alcohol, in flower development and pollen tube growth of apple (Malus domestica). Transgenic 'Greensleeves' apple trees with decreased sorbitol synthesis had abnormal stamen development, a decreased pollen germination rate and reduced pollen tube growth, which were all closely related to lower sorbitol concentrations in stamens...
October 13, 2017: New Phytologist
https://www.readbyqxmd.com/read/29027038/rescue-of-outer-hair-cells-with-antisense-oligonucleotides-in-usher-mice-is-dependent-on-age-of-treatment
#10
Abhilash Ponnath, Frederic F Depreux, Francine M Jodelka, Frank Rigo, Hamilton E Farris, Michelle L Hastings, Jennifer J Lentz
The absence of functional outer hair cells is a component of several forms of hereditary hearing impairment, including Usher syndrome, the most common cause of concurrent hearing and vision loss. Antisense oligonucleotide (ASO) treatment of mice with the human Usher mutation, Ush1c c.216G>A, corrects gene expression and significantly improves hearing, as measured by auditory-evoked brainstem responses (ABRs), as well as inner and outer hair cell (IHC and OHC) bundle morphology. However, it is not clear whether the improvement in hearing achieved by ASO treatment involves the functional rescue of outer hair cells...
October 12, 2017: Journal of the Association for Research in Otolaryngology: JARO
https://www.readbyqxmd.com/read/29023168/development-and-characterization-of-cationic-solid-lipid-nanoparticles-for-co-delivery-of-pemetrexed-and-mir-21-antisense-oligonucleotide-to-glioblastoma-cells
#11
Berrin Küçüktürkmen, Asuman Bozkır
The practical use of solid lipid nanoparticles (SLNs) in research has been highlighted in the literature, but few reports have combined SLNs with miRNA-based therapy and chemotherapy. We aimed to prepare cationic SLNs (cSLNs) to load anti-miR-21 oligonucleotide and pemetrexed for glioblastoma therapy in vitro. cSLNs were employed to encapsulate both pemetrexed and anti-miR-21 by a high pressure homogenization method, and then the properties of cSLNs were characterized. We studied cellular uptake and cytotoxicity properties of cSLNs in U87MG cells...
October 12, 2017: Drug Development and Industrial Pharmacy
https://www.readbyqxmd.com/read/29021226/attenuation-of-accelerated-renal-cystogenesis-in-pkd1-mice-by-renin-angiotensin-system-blockade
#12
Wayne R Fitzgibbon, Yujing Dang, Marlene A Bunni, Catalin F Baicu, Michael R Zile, Adam E Mullick, Takamitsu Saigusa
BACKGROUND: The intrarenal renin angiotensin system (RAS) is activated in polycystic kidney disease. We have recently shown in the Pkd1 mouse that Gen 2 antisense oligonucleotide (ASO), which suppresses angiotensinogen (Agt) synthesis, is efficacious in slowing kidney cyst formation compared to lisinopril. The aim of this current study was to determine 1) if unilateral nephrectomy accelerates cystogenesis in Pkd1 mice (as previously shown in cilia knockout mice), and 2) whether Agt ASO can slow the progression in this accelerated cystic mouse model...
October 11, 2017: American Journal of Physiology. Renal Physiology
https://www.readbyqxmd.com/read/28989608/rna-splicing-process-analysis-for-identifying-antisense-oligonucleotide-inhibitors-with-padlock-probe-based-isothermal-amplification
#13
Xiaojun Ren, Ruijie Deng, Lida Wang, Kaixiang Zhang, Jinghong Li
RNA splicing, which mainly involves two transesterification steps, is a fundamental process of gene expression and its abnormal regulation contributes to serious genetic diseases. Antisense oligonucleotides (ASOs) are genetic control tools that can be used to specifically control genes through alteration of the RNA splicing pathway. Despite intensive research, how ASOs or various other factors influence the multiple processes of RNA splicing still remains obscure. This is largely due to an inability to analyze the splicing efficiency of each step in the RNA splicing process with high sensitivity...
August 1, 2017: Chemical Science
https://www.readbyqxmd.com/read/28984319/angiopoietin-like-3-in-lipoprotein-metabolism
#14
REVIEW
Sander Kersten
Triglycerides and cholesterol circulate in the bloodstream as part of various lipoprotein particles. Three members of the angiopoietin-like (ANGPTL) protein family - ANGPTL3, ANGPTL4 and ANGPTL8 - have emerged as important regulators of plasma lipoprotein levels by inhibiting the enzyme lipoprotein lipase. Here, I review the role of ANGPTL3 in lipoprotein metabolism. In contrast to ANGPTL4 and ANGPTL8, ANGPTL3 is exclusively produced in the liver and can therefore be classified as a true hepatokine. ANGPTL3 cooperates with ANGPTL8 to inhibit lipoprotein lipase and is mostly active after feeding, whereas ANGPTL4 is mostly active after fasting...
October 6, 2017: Nature Reviews. Endocrinology
https://www.readbyqxmd.com/read/28983837/treatment-advances-in-spinal-muscular-atrophy
#15
REVIEW
Diana Bharucha-Goebel, Petra Kaufmann
PURPOSE OF REVIEW: Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development. RECENT FINDINGS: Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials...
October 6, 2017: Current Neurology and Neuroscience Reports
https://www.readbyqxmd.com/read/28981879/activation-of-a-cryptic-5-splice-site-reverses-the-impact-of-pathogenic-splice-site-mutations-in-the-spinal-muscular-atrophy-gene
#16
Natalia N Singh, José Bruno Del Rio-Malewski, Diou Luo, Eric W Ottesen, Matthew D Howell, Ravindra N Singh
Spinal muscular atrophy (SMA) is caused by deletions or mutations of the Survival Motor Neuron 1 (SMN1) gene coupled with predominant skipping of SMN2 exon 7. The only approved SMA treatment is an antisense oligonucleotide that targets the intronic splicing silencer N1 (ISS-N1), located downstream of the 5' splice site (5'ss) of exon 7. Here, we describe a novel approach to exon 7 splicing modulation through activation of a cryptic 5'ss (Cr1). We discovered the activation of Cr1 in transcripts derived from SMN1 that carries a pathogenic G-to-C mutation at the first position (G1C) of intron 7...
September 15, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28978026/enhanced-antiproliferative-activity-of-antibody-functionalized-polymeric-nanoparticles-for-targeted-delivery-of-anti-mir-21-to-her2-positive-gastric-cancer
#17
Feng-Lei Wu, Jian Zhang, Wei Li, Bao-Xiang Bian, Yi-Dong Hong, Zi-Yan Song, Hui-Yu Wang, Fang-Bo Cui, Ru-Tian Li, Qin Liu, Xiao-Dong Jiang, Xiao-Min Li, Jun-Nian Zheng
MiR-21 is an oncogenic miR frequently elevated in gastric cancer. Overexpression of miR-21 decreases the sensitivity of gastric cancer cells to trastuzumab, which is a humanized monoclonal antibody targeting human epidermal growth factor receptor 2. However, optimization of miRNA or its anti-miRNA oligonucleotides (AMOs) for delivery is a challenge. Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including AMOs. This study is a continuation of our earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with HER2 receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21)...
September 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/28977508/nucleic-acid-binding-proteins-affect-the-subcellular-distribution-of-phosphorothioate-antisense-oligonucleotides
#18
Jeffrey K Bailey, Wen Shen, Xue-Hai Liang, Stanley T Crooke
Antisense oligonucleotides (ASOs) are versatile tools that can regulate multiple steps of RNA biogenesis in cells and living organisms. Significant improvements in delivery, potency, and stability have been achieved through modifications within the oligonucleotide backbone, sugar and heterocycles. However, these modifications can profoundly affect interactions between ASOs and intracellular proteins in ways that are only beginning to be understood. Here, we report that ASOs with specific backbone and sugar modifications can become localized to cytoplasmic ribonucleoprotein granules such as stress granules and those seeded by the aggregation of specific ASO-binding proteins such as FUS/TLS (FUS) and PSF/SFPQ (PSF)...
August 9, 2017: Nucleic Acids Research
https://www.readbyqxmd.com/read/28977438/spinal-muscular-atrophy-antisense-oligonucleotide-therapy-opens-the-door-to-an-integrated-therapeutic-landscape
#19
Matthew J A Wood, Kevin Talbot, Melissa Bowerman
Spinal muscular atrophy (SMA) is a devastating neuromuscular disorder characterized by loss of spinal cord motor neurons, muscle atrophy and infantile death or severe disability. It is caused by severe reduction of the ubiquitously expressed survival motor neuron (SMN) protein, owing to loss of the SMN1 gene. This would be completely incompatible with survival without the presence of a quasi-identical duplicated gene, SMN2, specific to humans. SMN2 harbours a silent point mutation that favours the production of transcripts lacking exon 7 and a rapidly degraded non-functional SMNΔ7 protein, but from which functional full length SMN protein is produced at very low levels (∼10%)...
October 1, 2017: Human Molecular Genetics
https://www.readbyqxmd.com/read/28976632/mir-catch-identifies-biologically-active-mirna-regulators-of-the-pro-survival-gene-xiap-in-chinese-hamster-ovary-cells
#20
Alan Griffith, Paul S Kelly, Sebastian Vencken, Nga T Lao, Catherine M Greene, Martin Clynes, Niall Barron
Genetic engineering of mammalian cells is of interest as a means to boost bio-therapeutic protein yield. X-linked inhibitor of apoptosis (XIAP) overexpression has previously been shown to enhance CHO cell growth and prolong culture longevity while additionally boosting productivity. We confirmed this across a range of recombinant products (SEAP, EPO and IgG). However, stable over-expression of an engineering transgene competes for the cells translational machinery potentially compromising product titre. MicroRNAs are attractive genetic engineering candidates given their non-coding nature and ability to regulate multiple genes simultaneously, thereby relieving the translational burden associated with stable overexpression of a protein-encoding gene...
October 4, 2017: Biotechnology Journal
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