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Exon skipping therapy

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https://www.readbyqxmd.com/read/28915335/ecm-related-myopathies-and-muscular-dystrophies-pros-and-cons-of-protein-therapies
#1
Pam M Van Ry, Tatiana M Fontelonga, Pamela Barraza-Flores, Apurva Sarathy, Andreia M Nunes, Dean J Burkin
Extracellular matrix (ECM) myopathies and muscular dystrophies are a group of genetic diseases caused by mutations in genes encoding proteins that provide critical links between muscle cells and the extracellular matrix. These include structural proteins of the ECM, muscle cell receptors, enzymes, and intracellular proteins. Loss of adhesion within the myomatrix results in progressive muscle weakness. For many ECM muscular dystrophies, symptoms can occur any time after birth and often result in reduced life expectancy...
September 12, 2017: Comprehensive Physiology
https://www.readbyqxmd.com/read/28834590/abstracts
#2
Megan A Waldrop, Felecia Gumienny, Robert B Weiss, Kevin M Flanigan
INTRODUCTION: The reading frame rule suggests that Duchenne muscular dystrophy (DMD) results from DMD mutations causing an out-of-frame transcript, whereas the milder Becker muscular dystrophy results from mutations causing an in-frame transcript. However, predicted nonsense mutations may instead result in altered splicing and in-frame transcripts. CASE REPORT: Here we report a 10-year-old boy with a predicted nonsense mutation in exon 42 who had a 6-minute walk time of 157% of that of age matched DMD controls, characterized as intermediate muscular dystrophy...
August 23, 2017: Muscle & Nerve
https://www.readbyqxmd.com/read/28813090/brazilian-consensus-on-duchenne-muscular-dystrophy-part-1-diagnosis-steroid-therapy-and-perspectives
#3
Alexandra P Q C Araujo, Alzira A S de Carvalho, Eduardo B U Cavalcanti, Jonas Alex M Saute, Elmano Carvalho, Marcondes C França, Alberto R M Martinez, Monica de M M Navarro, Anamarli Nucci, Maria Bernadete D de Resende, Marcus Vinicius M Gonçalves, Juliana Gurgel-Giannetti, Rosana H Scola, Cláudia F da R Sobreira, Umbertina C Reed, Edmar Zanoteli
Significant advances in the understanding and management of Duchenne muscular dystrophy (DMD) took place since international guidelines were published in 2010. Our objective was to provide an evidence-based national consensus statement for multidisciplinary care of DMD in Brazil. A combination of the Delphi technique with a systematic review of studies from 2010 to 2016 was employed to classify evidence levels and grade of recommendations. Our recommendations were divided in two parts. We present Part 1 here, where we describe the guideline methodology and overall disease concepts, and also provide recommendations on diagnosis, steroid therapy and new drug treatment perspectives for DMD...
August 2017: Arquivos de Neuro-psiquiatria
https://www.readbyqxmd.com/read/28796573/development-of-exon-skipping-therapies-for-duchenne-muscular-dystrophy-a-critical-review-and-a-perspective-on-the-outstanding-issues
#4
Annemieke Aartsma-Rus, Volker Straub, Robert Hemmings, Manuel Haas, Gabriele Schlosser-Weber, Violeta Stoyanova-Beninska, Eugenio Mercuri, Francesco Muntoni, Bruno Sepodes, Elizabeth Vroom, Pavel Balabanov
Duchenne muscular dystrophy (DMD) is a rare, severe, progressive muscle-wasting disease leading to disability and premature death. Patients lack the muscle membrane-stabilizing protein dystrophin. Antisense oligonucleotide (AON)-mediated exon skipping is a therapeutic approach that aims to induce production of partially functional dystrophins. Recently, an AON targeting exon 51 became the first of its class to be approved by the United States regulators [Food and Drug Administration (FDA)] for the treatment of DMD...
August 10, 2017: Nucleic Acid Therapeutics
https://www.readbyqxmd.com/read/28757336/double-trouble-a-case-series-on-concomitant-genetic-aberrations-in-nsclc
#5
REVIEW
Nele Van Der Steen, Yves Mentens, Marc Ramael, Leticia G Leon, Paul Germonpré, Jose Ferri, David R Gandara, Elisa Giovannetti, Godefridus J Peters, Patrick Pauwels, Christian Rolfo
Several oncogenic drivers have been identified in non-small cell lung cancer. Targeted therapies for these aberrations have already been successfully developed and implemented in clinical practice. Owing to improved sensitivity in genetic testing, more and more tumors with multiple driver mutations are identified, resulting in dilemmas for treating physicians whether and which targeted therapy to use. In this case series, we provide an overview of patients with intrinsic double mutations in oncogenic drivers and their reported response to targeted therapies, with a focus on epidermal growth factor receptor, anaplastic lymphoma kinase, cMET, and Kirsten rat sarcoma viral oncogene...
July 6, 2017: Clinical Lung Cancer
https://www.readbyqxmd.com/read/28742140/short-16-mer-locked-nucleic-acid-splice-switching-oligonucleotides-restore-dystrophin-production-in-duchenne-muscular-dystrophy-myotubes
#6
Vanessa Borges Pires, Ricardo Simões, Kamel Mamchaoui, Célia Carvalho, Maria Carmo-Fonseca
Splice-switching antisense oligonucleotides (SSOs) offer great potential for RNA-targeting therapies, and two SSO drugs have been recently approved for treating Duchenne Muscular Dystrophy (DMD) and Spinal Muscular Atrophy (SMA). Despite promising results, new developments are still needed for more efficient chemistries and delivery systems. Locked nucleic acid (LNA) is a chemically modified nucleic acid that presents several attractive properties, such as high melting temperature when bound to RNA, potent biological activity, high stability and low toxicity in vivo...
2017: PloS One
https://www.readbyqxmd.com/read/28666123/splicing-correcting-therapy-for-sma
#7
Lili Wan, Gideon Dreyfuss
Spinal muscular atrophy (SMA) is caused by deficiency of SMN protein, which is crucial for spliceosome subunits biogenesis. Most SMA patients have SMN1 deletions, leaving SMN2 as sole SMN source; however, a C→T substitution converts an exonic-splicing enhancer (ESE) to a silencer (ESS), causing frequent exon7 skipping in SMN2 pre-mRNA and yielding a truncated protein. Antisense treatment to SMN2 intron7-splicing silencer (ISS) improves SMN expression and motor function. To view this Bench to Bedside, open or download the PDF...
June 29, 2017: Cell
https://www.readbyqxmd.com/read/28663100/a-new-aav10-u7-mediated-gene-therapy-prolongs-survival-and-restores-function-in-an-als-mouse-model
#8
Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD)...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28633548/polyquaternium-mediated-delivery-of-morpholino-oligonucleotides-for-exon-skipping-in-vitro-and-in-mdx-mice
#9
Mingxing Wang, Bo Wu, Sapana N Shah, Peijuan Lu, Qilong Lu
Antisense oligonucleotide therapy for Duchenne muscular dystrophy has shown great potential in preclinical and clinical trials, but its therapeutic applications are still limited due to inefficient delivery. In this study, we investigated a few polyquaterniums (PQs) with different size and composition for their potential to improve delivery performance of an antisense phosphorodiamidate morpholino oligomer (PMO) both in vitro and in vivo. The results showed that Luviquat(TM) series, especially PQ-1 and PQ-3, promoted the exon-skipping efficiency comparable to Endoporter-mediated PMO delivery in vitro...
November 2017: Drug Delivery
https://www.readbyqxmd.com/read/28624223/evaluation-of-mybpc3-trans-splicing-and-gene-replacement-as-therapeutic-options-in-human-ipsc-derived-cardiomyocytes
#10
Maksymilian Prondzynski, Elisabeth Krämer, Sandra D Laufer, Aya Shibamiya, Ole Pless, Frederik Flenner, Oliver J Müller, Julia Münch, Charles Redwood, Arne Hansen, Monica Patten, Thomas Eschenhagen, Giulia Mearini, Lucie Carrier
Gene therapy is a promising option for severe forms of genetic diseases. We previously provided evidence for the feasibility of trans-splicing, exon skipping, and gene replacement in a mouse model of hypertrophic cardiomyopathy (HCM) carrying a mutation in MYBPC3, encoding cardiac myosin-binding protein C (cMyBP-C). Here we used human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from an HCM patient carrying a heterozygous c.1358-1359insC MYBPC3 mutation and from a healthy donor. HCM hiPSC-CMs exhibited ∼50% lower MYBPC3 mRNA and cMyBP-C protein levels than control, no truncated cMyBP-C, larger cell size, and altered gene expression, thus reproducing human HCM features...
June 16, 2017: Molecular Therapy. Nucleic Acids
https://www.readbyqxmd.com/read/28575652/mutations-in-kdsr-cause-recessive-progressive-symmetric-erythrokeratoderma
#11
Lynn M Boyden, Nicholas G Vincent, Jing Zhou, Ronghua Hu, Brittany G Craiglow, Susan J Bayliss, Ilana S Rosman, Anne W Lucky, Luis A Diaz, Lowell A Goldsmith, Amy S Paller, Richard P Lifton, Susan J Baserga, Keith A Choate
The discovery of new genetic determinants of inherited skin disorders has been instrumental to the understanding of epidermal function, differentiation, and renewal. Here, we show that mutations in KDSR (3-ketodihydrosphingosine reductase), encoding an enzyme in the ceramide synthesis pathway, lead to a previously undescribed recessive Mendelian disorder in the progressive symmetric erythrokeratoderma spectrum. This disorder is characterized by severe lesions of thick scaly skin on the face and genitals and thickened, red, and scaly skin on the hands and feet...
June 1, 2017: American Journal of Human Genetics
https://www.readbyqxmd.com/read/28566768/moving-towards-successful-exon-skipping-therapy-for-duchenne-muscular-dystrophy
#12
REVIEW
Akinori Nakamura
Duchenne muscular dystrophy (DMD) is an X chromosome-linked lethal muscular disorder with progressing muscle wasting and weakness caused by mutations in the gene encoding a subsarcolemmal protein dystrophin. For a long time, there was no effective cure; however, advances in molecular biology have allowed the development of radical treatment approaches. Among them, exon-skipping therapy using antisense oligonucleotides is very promising, because it corrects the reading frame of the dystrophin-encoding gene and restores protein expression, resulting in the conversion of DMD to a clinically milder form, Becker muscular dystrophy (BMD)...
October 2017: Journal of Human Genetics
https://www.readbyqxmd.com/read/28555643/development-of-an-orally-available-inhibitor-of-clk1-for-skipping-a-mutated-dystrophin-exon-in-duchenne-muscular-dystrophy
#13
Yukiya Sako, Kensuke Ninomiya, Yukiko Okuno, Masayasu Toyomoto, Atsushi Nishida, Yuka Koike, Kenji Ohe, Isao Kii, Suguru Yoshida, Naohiro Hashimoto, Takamitsu Hosoya, Masafumi Matsuo, Masatoshi Hagiwara
Duchenne muscular dystrophy (DMD) is a fatal progressive muscle-wasting disease. Various attempts are underway to convert severe DMD to a milder phenotype by modulating the splicing of the dystrophin gene and restoring its expression. In our previous study, we reported TG003, an inhibitor of CDC2-like kinase 1 (CLK1), as a splice-modifying compound for exon-skipping therapy; however, its metabolically unstable feature hinders clinical application. Here, we show an orally available inhibitor of CLK1, named TG693, which promoted the skipping of the endogenous mutated exon 31 in DMD patient-derived cells and increased the production of the functional exon 31-skipped dystrophin protein...
May 30, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28526070/the-golden-retriever-model-of-duchenne-muscular-dystrophy
#14
REVIEW
Joe N Kornegay
Duchenne muscular dystrophy (DMD) is an X-linked disease caused by mutations in the DMD gene and loss of the protein dystrophin. The absence of dystrophin leads to myofiber membrane fragility and necrosis, with eventual muscle atrophy and contractures. Affected boys typically die in their second or third decade due to either respiratory failure or cardiomyopathy. Despite extensive attempts to develop definitive therapies for DMD, the standard of care remains prednisone, which has only palliative benefits. Animal models, mainly the mdx mouse and golden retriever muscular dystrophy (GRMD) dog, have played a key role in studies of DMD pathogenesis and treatment development...
May 19, 2017: Skeletal Muscle
https://www.readbyqxmd.com/read/28505980/creation-of-a-novel-humanized-dystrophic-mouse-model-of-duchenne-muscular-dystrophy-and-application-of-a-crispr-cas9-gene-editing-therapy
#15
Courtney S Young, Ekaterina Mokhonova, Marbella Quinonez, April D Pyle, Melissa J Spencer
Duchenne muscular dystrophy is caused by mutations in DMD which disrupt the reading frame. Therapeutic strategies that restore DMD's reading frame, such as exon skipping and CRISPR/Cas9, need to be tested in the context of the human DMD sequence in vivo. We have developed a novel dystrophic mouse model by using CRISPR/Cas9 to delete exon 45 in the human DMD gene in hDMD mice, which places DMD out-of-frame. We have utilized this model to demonstrate that our clinically-relevant CRISPR/Cas9 platform, which targets deletion of human DMD exons 45-55, can be directly applied in vivo to restore dystrophin...
2017: Journal of Neuromuscular Diseases
https://www.readbyqxmd.com/read/28502721/met-exon-14-skipping-mutations-in-lung-adenocarcinoma-clinicopathologic-implications-and-prognostic-values
#16
Geun Dong Lee, Seung Eun Lee, Doo-Yi Oh, Dan-Bi Yu, Hae Min Jeong, Jooseok Kim, Sungyoul Hong, Hun Soon Jung, Ensel Oh, Ji-Young Song, Mi-Sook Lee, Mingi Kim, Kyungsoo Jung, Jhingook Kim, Young Kee Shin, Yoon-La Choi, Hyeong Ryul Kim
INTRODUCTION: Response to mesenchymal-epithelial transition (MET) inhibitors in NSCLC with mesenchymal-epithelial transition gene (MET) exon 14 skipping (METex14) has fueled molecular screening efforts and the search for optimal therapies. However, further work is needed to refine the clinicopathologic and prognostic implications of METex14 skipping. METHODS: Among 795 East Asian patients who underwent a surgical procedure for NSCLC, we screened 45 patients with quintuple-negative (EGFR-negative/KRAS-negative/anaplastic lymphoma kinase gene [ALK]-negative/ROS1-negative/ret proto-oncogene [RET]-negative) lung adenocarcinomas by using reverse-transcriptase polymerase chain reaction and found 17 patients (37...
August 2017: Journal of Thoracic Oncology
https://www.readbyqxmd.com/read/28485722/how-the-discovery-of-iss-n1-led-to-the-first-medical-therapy-for-spinal-muscular-atrophy
#17
REVIEW
N N Singh, M D Howell, E J Androphy, R N Singh
Spinal muscular atrophy (SMA), a prominent genetic disease of infant mortality, is caused by low levels of survival motor neuron (SMN) protein owing to deletions or mutations of the SMN1 gene. SMN2, a nearly identical copy of SMN1 present in humans, cannot compensate for the loss of SMN1 because of predominant skipping of exon 7 during pre-mRNA splicing. With the recent US Food and Drug Administration approval of nusinersen (Spinraza), the potential for correction of SMN2 exon 7 splicing as an SMA therapy has been affirmed...
May 9, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28398005/nanotherapy-for-duchenne-muscular-dystrophy
#18
REVIEW
Michael E Nance, Chady H Hakim, N Nora Yang, Dongsheng Duan
Duchenne muscular dystrophy (DMD) is a lethal X-linked childhood muscle wasting disease caused by mutations in the dystrophin gene. Nanobiotechnology-based therapies (such as synthetic nanoparticles and naturally existing viral and nonviral nanoparticles) hold great promise to replace and repair the mutated dystrophin gene and significantly change the disease course. While a majority of DMD nanotherapies are still in early preclinical development, several [such as adeno-associated virus (AAV)-mediated systemic micro-dystrophin gene therapy] are advancing for phase I clinical trials...
April 11, 2017: Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology
https://www.readbyqxmd.com/read/28364245/systemic-delivery-of-morpholinos-to-skip-multiple-exons-in-a-dog-model-of-duchenne-muscular-dystrophy
#19
Rika Maruyama, Yusuke Echigoya, Oana Caluseriu, Yoshitsugu Aoki, Shin'ichi Takeda, Toshifumi Yokota
Exon-skipping therapy is an emerging approach that uses synthetic DNA-like molecules called antisense oligonucleotides (AONs) to splice out frame-disrupting parts of mRNA, restore the reading frame, and produce truncated yet functional proteins. Multiple exon skipping utilizing a cocktail of AONs can theoretically treat 80-90% of patients with Duchenne muscular dystrophy (DMD). The success of multiple exon skipping by the systemic delivery of a cocktail of AONs called phosphorodiamidate morpholino oligomers (PMOs) in a DMD dog model has made a significant impact on the development of therapeutics for DMD, leading to clinical trials of PMO-based drugs...
2017: Methods in Molecular Biology
https://www.readbyqxmd.com/read/28361099/a-de-novo-splice-site-mutation-in-ehmt1-resulting-in-kleefstra-syndrome-with-pharmacogenomics-screening-and-behavior-therapy-for-regressive-behaviors
#20
Amit Kumar Mitra, Jessica Dodge, Jody Van Ness, Israel Sokeye, Brian Van Ness
BACKGROUND: Kleefstra syndrome (KS) is a rare autosomal dominant developmental disability, caused by microdeletions or intragenic mutations within the epigenetic regulator gene EHMT1 (euchromatic histone lysine N-methyltransferase 1). In addition to common features of autism, young adult regressive behaviors have been reported. However, the genetic downstream effects of the reported deletions or mutations on KS phenotype have not yet been completely explored. While genetic backgrounds affecting drug metabolism can have a profound effect on therapeutic interventions, pharmacogenomic variations are seldom considered in directing psychotropic therapies...
March 2017: Molecular Genetics & Genomic Medicine
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