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Exon skipping therapy

Svitlana Pasteuning-Vuhman, Johanna Boertje-van der Meulen, Maaike van Putten, Maurice Overzier, Peter Ten Dijke, Szymon M Kiełbasa, Wibowo Arindrarto, Ron Wolterbeek, Ksenia V Lezhnina, Ivan V Ozerov, Aleksandr M Aliper, Willem M Hoogaars, Annemieke Aartsma-Rus, Cindy J M Loomans
Skeletal muscle fibrosis and impaired muscle regeneration are major contributors to muscle wasting in Duchenne muscular dystrophy (DMD). Muscle growth is negatively regulated by myostatin (MSTN) and activins. Blockage of these pathways may improve muscle quality and function in DMD. Antisense oligonucleotides (AONs) were designed specifically to block the function of ALK4, a key receptor for the MSTN/activin pathway in skeletal muscle. AON-induced exon skipping resulted in specific Alk4 down-regulation, inhibition of MSTN activity, and increased myoblast differentiation in vitro Unexpectedly, a marked decrease in muscle mass (10%) was found after Alk4 AON treatment in mdx mice...
October 12, 2016: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
T Uo, H Dvinge, C C Sprenger, R K Bradley, P S Nelson, S R Plymate
The presence of intact ligand-binding domain (LBD) ensures the strict androgen-dependent regulation of androgen receptor (AR): binding of androgen induces structural reorganization of LBD resulting in release of AR from HSP90, suppression of nuclear export which otherwise dominates over import and nuclear translocation of AR as a transcription factor. Thus, loss or defects of the LBD abolish constraint from un-liganded LBD as exemplified by constitutively active AR variants (AR-Vs), which are associated with emerging resistance mechanism to anti-AR therapy in castration-resistant prostate cancer (mCRPC)...
October 3, 2016: Oncogene
Samuel J Klempner, Ali Borghei, Behrooz Hakimian, Siraj M Ali, Sai-Hong Ignatius Ou
INTRODUCTION: A significant portion of non-small cell lung cancers with MET exon14 skipping alterations are sensitive to small molecule MET tyrosine kinase inhibitors. However, the incidence and management of brain metastases in this molecular subset is unknown and represents an unmet clinical need. METHODS: Hybrid capture based comprehensive genomic profiling identified a patient with a MET exon14 skipping alteration and serial MRI imaging was utilized to follow intracranial disease during crizotinib and subsequent cabozantinib therapy...
September 27, 2016: Journal of Thoracic Oncology
Daniela Scalet, Dario Balestra, Sara Rohban, Matteo Bovolenta, Daniela Perrone, Francesco Bernardi, Stefano Campaner, Mirko Pinotti
The c.2101A>G synonymous change (p.G674G) in the gene for ATR, a key player in the DNA-damage response, has been the first identified genetic cause of Seckel Syndrome (SS), an orphan disease characterized by growth and mental retardation. This mutation mainly causes exon 9 skipping, through an ill-defined mechanism. Through ATR minigene expression studies, we demonstrated that the detrimental effect of this mutation (6±1% of correct transcripts only) depends on the poor exon 9 definition (47±4% in the ATR(wt) context), because the change was ineffective when the weak 5' or the 3' splice sites (ss) were strengthened (scores from 0...
September 14, 2016: Biochimica et Biophysica Acta
Shouta Miyatake, Yuko Shimizu-Motohashi, Shin'ichi Takeda, Yoshitsugu Aoki
Duchenne muscular dystrophy (DMD), an incurable and a progressive muscle wasting disease, is caused by the absence of dystrophin protein, leading to recurrent muscle fiber damage during contraction. The inflammatory response to fiber damage is a compelling candidate mechanism for disease exacerbation. The only established pharmacological treatment for DMD is corticosteroids to suppress muscle inflammation, however this treatment is limited by its insufficient therapeutic efficacy and considerable side effects...
2016: Drug Design, Development and Therapy
Alice Todeschini, Francesca Gualandi, Cecilia Trabanelli, Annarita Armaroli, Anna Ravani, Marina Fanin, Silvia Rota, Luca Bello, Alessandra Ferlini, Elena Pegoraro, Alessandro Padovani, Massimiliano Filosto
We describe a 29-year-old patient who complained of left thigh muscle weakness since he was 23 and of moderate proximal weakness of both lower limbs with difficulty in climbing stairs and running since he was 27. Mild weakness of iliopsoas and quadriceps muscles and muscle atrophy of both the distal forearm and thigh were observed upon clinical examination. He harboured a novel c.1150-3C>G substitution in the DMD gene, affecting the intron 10 acceptor splice site and causing exon 11 skipping and an out-of-frame transcript...
October 2016: Neuromuscular Disorders: NMD
Shiyong Li, Yoon-La Choi, Zhuolin Gong, Xiao Liu, Maruja Lira, Zhengyan Kan, Ensel Oh, Jian Wang, Jason C Ting, Xiangsheng Ye, Christoph Reinhart, Xiaoqiao Liu, Yunfei Pei, Wei Zhou, Ronghua Chen, Shijun Fu, Gang Jin, Awei Jiang, Julio Fernandez, James Hardwick, Min Woong Kang, Hoseok I, Hancheng Zheng, Jhingook Kim, Mao Mao
INTRODUCTION: The incidence rate of lung adenocarcinoma (LUAD), the predominant histological subtype of lung cancer, is elevated in Asians, particularly in female nonsmokers. The mutation patterns in LUAD in Asians might be distinct from those in LUAD in whites. METHODS: We profiled 271 resected LUAD tumors (mainly stage I) to characterize the genomic landscape of LUAD in Asians with a focus on female nonsmokers. RESULTS: Mutations in EGFR, KRAS, erb-b2 receptor tyrosine kinase 2 gene (ERBB2), and BRAF; gene fusions involving anaplastic lymphoma receptor tyrosine kinase gene (ALK), ROS1, and ret proto-oncogene (RET); and Met Proto-Oncogene Tyrosine Kinase (MET) exon 14 skipping were the major drivers in LUAD in Asians, exhibiting mutually exclusive and differing prevalence from those reported in studies of LUAD in non-Asians...
September 9, 2016: Journal of Thoracic Oncology
Jacqueline N Robinson-Hamm, Charles A Gersbach
Duchenne muscular dystrophy is one of the most common inherited genetic diseases and is caused by mutations to the DMD gene that encodes the dystrophin protein. Recent advances in genome editing and gene therapy offer hope for the development of potential therapeutics. Truncated versions of the DMD gene can be delivered to the affected tissues with viral vectors and show promising results in a variety of animal models. Genome editing with the CRISPR/Cas9 system has recently been used to restore dystrophin expression by deleting one or more exons of the DMD gene in patient cells and in a mouse model that led to functional improvement of muscle strength...
September 2016: Human Genetics
Maria Sofia Falzarano, Domenico D'Amario, Andrea Siracusano, Massimo Massetti, Antonio Amodeo, Federica La Neve, Camilla Reina Maroni, Eugenio Mercuri, Hana Osman, Chiara Scotton, Annarita Armaroli, Rachele Rossi, Rita Selvatici, Filippo Crea, Alessandra Ferlini
A ready source of autologous myogenic cells is of vital importance for drug screening and functional genetic studies in Duchenne Muscular Dystrophy (DMD), a rare disease caused by a variety of dystrophin gene mutations. As stem cells (SCs) can be easily and non-invasively obtained from urine specimens, we set out to determine whether they could be myogenic-induced and useful in DMD research. To this end, we isolated stem cells from the urine of two healthy donors and one patient with DMD, and performed surface-marker characterization, myogenic differentiation (MyoD), and then transfection with antisense oligoribonucletoides to test for exon skipping and protein restoration...
August 16, 2016: Human Gene Therapy
John Cw Hildyard, Dominic J Wells
Exon-skipping via synthetic antisense oligonucleotides represents one of the most promising potential therapies for Duchenne muscular dystrophy (DMD), yet this approach is highly sequence-specific and thus each oligonucleotide is of benefit to only a subset of patients. The discovery that dystrophin mRNA is subject to translational suppression by the microRNA miR31, and that miR31 is elevated in the muscle of DMD patients, raises the possibility that the same oligonucleotide chemistries employed for exon skipping could be directed toward relieving this translational block...
2016: PLoS Currents
Jean K Mah
Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood. It is caused by mutations of the DMD gene, leading to progressive muscle weakness, loss of independent ambulation by early teens, and premature death due to cardiorespiratory complications. The diagnosis can usually be made after careful review of the history and examination of affected boys presenting with developmental delay, proximal weakness, and elevated serum creatine kinase, plus confirmation by muscle biopsy or genetic testing...
2016: Neuropsychiatric Disease and Treatment
Pauline Roy, Fredérique Rau, Julien Ochala, Julien Messéant, Bodvael Fraysse, Jeanne Lainé, Onnik Agbulut, Gillian Butler-Browne, Denis Furling, Arnaud Ferry
BACKGROUND: The greater susceptibility to contraction-induced skeletal muscle injury (fragility) is an important dystrophic feature and tool for testing preclinic dystrophin-based therapies for Duchenne muscular dystrophy. However, how these therapies reduce the muscle fragility is not clear. METHODS: To address this question, we first determined the event(s) of the excitation-contraction cycle which is/are altered following lengthening (eccentric) contractions in the mdx muscle...
2016: Skeletal Muscle
Zhaiyi Zhang, Manli Shen, Paul J Gresch, Masoud Ghamari-Langroudi, Alexander G Rabchevsky, Ronald B Emeson, Stefan Stamm
The serotonin 2C receptor regulates food uptake, and its activity is regulated by alternative pre-mRNA splicing. Alternative exon skipping is predicted to generate a truncated receptor protein isoform, whose existence was confirmed with a new antiserum. The truncated receptor sequesters the full-length receptor in intracellular membranes. We developed an oligonucleotide that promotes exon inclusion, which increases the ratio of the full-length to truncated receptor protein. Decreasing the amount of truncated receptor results in the accumulation of full-length, constitutively active receptor at the cell surface...
2016: EMBO Molecular Medicine
Yuko Shimizu-Motohashi, Shouta Miyatake, Hirofumi Komaki, Shin'ichi Takeda, Yoshitsugu Aoki
Duchenne muscular dystrophy (DMD) is an X-linked progressive degenerative muscle disorder caused by the absence of dystrophin. There is no curative therapy, although innovative therapeutic approaches have been aggressively investigated over recent years. Currently, the international clinical trial registry platform for this disease has been constructed and clinical trials for innovative therapeutic approaches are underway. Among these, exon skipping and read-through of nonsense mutations are in the most advanced stages, with exon skipping theoretically applicable to a larger number of patients...
2016: American Journal of Translational Research
Cécile Peccate, Amédée Mollard, Maëva Le Hir, Laura Julien, Graham McClorey, Susan Jarmin, Anita Le Heron, George Dickson, Sofia Benkhelifa-Ziyyat, France Piétri-Rouxel, Matthew J Wood, Thomas Voit, Stéphanie Lorain
In preclinical models for Duchenne muscular dystrophy, dystrophin restoration during AAV-U7-mediated exon-skipping therapy was shown to decrease drastically after six months in treated muscles. This decline in efficacy is strongly correlated with loss of the therapeutic AAV genomes, probably due to alterations of the dystrophic myofiber membranes. To improve the membrane integrity of the dystrophic myofibers at the time of AAV-U7 injection, mdx muscles were pre-treated with a single dose of peptide-phosphorodiamidate morpholino (PPMO) antisense oligonucleotides that induced temporary dystrophin expression at the sarcolemma...
July 4, 2016: Human Molecular Genetics
Rebecca S Heist, Lecia V Sequist, Darrell Borger, Justin F Gainor, Ronald S Arellano, Long P Le, Dora Dias-Santagata, Jeffrey W Clark, Jeffrey A Engelman, Alice T Shaw, A John Iafrate
INTRODUCTION: MET proto-oncogene, receptor tyrosine kinase gene (MET) exon 14 skipping is a targetable alteration in lung cancer. Treatment with MET proto-oncogene, receptor tyrosine kinase inhibitor can cause dramatic responses in patients whose cancers have MET exon 14 skipping. Little is known, however, about acquired resistance in patients with MET exon 14 skipping. METHODS: Biopsy specimens obtained at baseline and at the time of progression for a patient being treated with crizotinib were compared using targeted next-generation sequencing to assess for mechanisms of resistance...
August 2016: Journal of Thoracic Oncology
Pattaranatcha Charnwichai, Patra Yeetong, Kanya Suphapeetiporn, Vichit Supornsilchai, Taninee Sahakitrungruang, Vorasuk Shotelersuk
BACKGROUND: Congenital adrenal hyperplasia (CAH) due to steroid 11β-hydroxylase deficiency (11β-OHD) is a rare form of CAH associated with low renin hypertension, hypokalemia, hyperandrogenemia and ambiguous genitalia in affected females. Herein we describe the clinical, hormonal and molecular characteristics of two Uzbekistan siblings with 11β-OHD and analyze the effects of a splicing mutation. CASE PRESENTATION: A 46,XX girl presented with genital ambiguity and low renin hypertension; her 46,XY brother presented with precocious puberty...
2016: BMC Endocrine Disorders
Bailey Miskew Nichols, Yoshitsugu Aoki, Mutsuki Kuraoka, Joshua J A Lee, Shin'ichi Takeda, Toshifumi Yokota
Duchenne muscular dystrophy (DMD) is one of the most common lethal genetic diseases worldwide, caused by mutations in the dystrophin (DMD) gene. Exon skipping employs short DNA/RNA-like molecules called antisense oligonucleotides (AONs) that restore the reading frame and produce shorter but functional proteins. However, exon skipping therapy faces two major hurdles: limited applicability (up to only 13% of patients can be treated with a single AON drug), and uncertain function of truncated proteins. These issues were addressed with a cocktail AON approach...
2016: Journal of Visualized Experiments: JoVE
Si-Yang Liu, Lan-Ying Gou, An-Na Li, Na-Na Lou, Hong-Fei Gao, Jian Su, Jin-Ji Yang, Xu-Chao Zhang, Yang Shao, Zhong-Yi Dong, Qing Zhou, Wen-Zhao Zhong, Yi-Long Wu
INTRODUCTION: Predictive biomarkers of mesenchymal-to-epithelial transition factor (MET)-targeted therapy remain elusive. Since the discovery of the MNNG HOS Transforming gene (MET) exon 14 mutation, it has been found to have the best potential to become one precise biomarker for MET-targeted therapy. Here, we present the unique characteristics of MET exon 14 mutations in Chinese patients with NSCLC. METHODS: A total of 1296 patients with NSCLC were screened for MET exon 14 mutations...
September 2016: Journal of Thoracic Oncology
Alice Masurel-Paulet, Amélie Piton, Sophie Chancenotte, Claire Redin, Christel Thauvin-Robinet, Yvan Henrenger, Delphine Minot, Audrey Creppy, Marie Ruffier-Bourdet, Julien Thevenon, Paul Kuentz, Daphné Lehalle, Aurore Curie, Gaelle Blanchard, Ezzat Ghosn, Marlene Bonnet, Mélanie Archimbaud-Devilliers, Frédéric Huet, Odile Perret, Nicole Philip, Jean-Louis Mandel, Laurence Faivre
Using targeted next generation sequencing, we have identified a splicing mutation (c.526-9_526-5del) in the SLC9A6 gene in a 9-year-old boy with mild intellectual disability (ID), microcephaly, and social interaction disabilities. This intronic microdeletion leads to the skipping of exon 3 and to an in-frame deletion of 26 amino acids in the TM4 domain. It segregates with cognitive impairment or learning difficulties in other members of the family. Mutations in SLC9A6 have been reported in X-linked Christianson syndrome associating severe to profound intellectual deficiency and an Angelman-like phenotype with microcephaly, absent speech, ataxia with progressive cerebellar atrophy, ophthalmoplegia, epilepsy, and neurological regression...
August 2016: American Journal of Medical Genetics. Part A
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