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DMD and CAS9

Hong-Hao Yu, Heng Zhao, Yu-Bo Qing, Wei-Rong Pan, Bao-Yu Jia, Hong-Ye Zhao, Xing-Xu Huang, Hong-Jiang Wei
Dystrophinopathy, including Duchenne muscle dystrophy (DMD) and Becker muscle dystrophy (BMD) is an incurable X-linked hereditary muscle dystrophy caused by a mutation in the DMD gene in coding dystrophin. Advances in further understanding DMD/BMD for therapy are expected. Studies on mdx mice and dogs with muscle dystrophy provide limited insight into DMD disease mechanisms and therapeutic testing because of the different pathological manifestations. Miniature pigs share similar physiology and anatomy with humans and are thus an excellent animal model of human disease...
October 9, 2016: International Journal of Molecular Sciences
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
Ignazio Maggio, Xiaoyu Chen, Manuel A F V Gonçalves
Duchenne muscular dystrophy (DMD) is a genetic disorder caused by mutations in the dystrophin-encoding DMD gene. The DMD gene, spanning over 2.4 megabases along the short arm of the X chromosome (Xp21.2), is the largest genetic locus known in the human genome. The size of DMD, combined with the complexity of the DMD phenotype and the extent of the affected tissues, begs for the development of novel, ideally complementary, therapeutic approaches. Genome editing based on the delivery of sequence-specific programmable nucleases into dystrophin-defective cells has recently enriched the portfolio of potential therapies under investigation...
2016: Genome Medicine
Michele P Calos
No abstract text is available yet for this article.
April 28, 2016: New England Journal of Medicine
Astrid Breitbart, Charles E Murry
There is still no curative treatment for Duchenne muscular dystrophy (DMD). In this issue of Cell Stem Cell, Young et al. (2016) demonstrate a genome editing approach applicable to 60% of DMD patients with CRISPR/Cas9 using one pair of guide RNAs.
April 7, 2016: Cell Stem Cell
Jerry R Mendell, Louise R Rodino-Klapac
A novel approach to gene correction by genome editing shows great promise as a treatment for Duchenne muscular dystrophy (DMD). CRISPR/Cas9 delivered by adeno-associated virus to a mouse model for DMD demonstrated improvement in function and histology.
May 2016: Cell Research
Courtney S Young, Michael R Hicks, Natalia V Ermolova, Haruko Nakano, Majib Jan, Shahab Younesi, Saravanan Karumbayaram, Chino Kumagai-Cresse, Derek Wang, Jerome A Zack, Donald B Kohn, Atsushi Nakano, Stanley F Nelson, M Carrie Miceli, Melissa J Spencer, April D Pyle
Mutations in DMD disrupt the reading frame, prevent dystrophin translation, and cause Duchenne muscular dystrophy (DMD). Here we describe a CRISPR/Cas9 platform applicable to 60% of DMD patient mutations. We applied the platform to DMD-derived hiPSCs where successful deletion and non-homologous end joining of up to 725 kb reframed the DMD gene. This is the largest CRISPR/Cas9-mediated deletion shown to date in DMD. Use of hiPSCs allowed evaluation of dystrophin in disease-relevant cell types. Cardiomyocytes and skeletal muscle myotubes derived from reframed hiPSC clonal lines had restored dystrophin protein...
April 7, 2016: Cell Stem Cell
Dwi U Kemaladewi, Ronald D Cohn
Duchenne muscular dystrophy (DMD) is a life-limiting neuromuscular disorder caused by mutations in the DMD gene encoding dystrophin. We discuss very recent studies that used CRISPR/Cas9 technology to 'snip out' mutated exons in DMD, restoring the reading frame of the gene. We also present cautionary aspects of translating this exciting technology into clinical practice.
March 2016: Trends in Molecular Medicine
Jean-Paul Iyombe-Engembe, Dominique L Ouellet, Xavier Barbeau, Joël Rousseau, Pierre Chapdelaine, Patrick Lagüe, Jacques P Tremblay
The CRISPR/Cas9 system is a great revolution in biology. This technology allows the modification of genes in vitro and in vivo in a wide variety of living organisms. In most Duchenne muscular dystrophy (DMD) patients, expression of dystrophin (DYS) protein is disrupted because exon deletions result in a frame shift. We present here the CRISPR-induced deletion (CinDel), a new promising genome-editing technology to correct the DMD gene. This strategy is based on the use of two gRNAs targeting specifically exons that precede and follow the patient deletion in the DMD gene...
2016: Molecular Therapy. Nucleic Acids
Ignazio Maggio, Luca Stefanucci, Josephine M Janssen, Jin Liu, Xiaoyu Chen, Vincent Mouly, Manuel A F V Gonçalves
Duchenne muscular dystrophy (DMD) is a fatal X-linked muscle-wasting disorder caused by mutations in the 2.4 Mb dystrophin-encoding DMD gene. The integration of gene delivery and gene editing technologies based on viral vectors and sequence-specific designer nucleases, respectively, constitutes a potential therapeutic modality for permanently repairing defective DMD alleles in patient-derived myogenic cells. Therefore, we sought to investigate the feasibility of combining adenoviral vectors (AdVs) with CRISPR/Cas9 RNA-guided nucleases (RGNs) alone or together with transcriptional activator-like effector nucleases (TALENs), for endogenous DMD repair through non-homologous end-joining (NHEJ)...
February 18, 2016: Nucleic Acids Research
Mohammadsharif Tabebordbar, Kexian Zhu, Jason K W Cheng, Wei Leong Chew, Jeffrey J Widrick, Winston X Yan, Claire Maesner, Elizabeth Y Wu, Ru Xiao, F Ann Ran, Le Cong, Feng Zhang, Luk H Vandenberghe, George M Church, Amy J Wagers
Frame-disrupting mutations in the DMD gene, encoding dystrophin, compromise myofiber integrity and drive muscle deterioration in Duchenne muscular dystrophy (DMD). Removing one or more exons from the mutated transcript can produce an in-frame mRNA and a truncated, but still functional, protein. In this study, we developed and tested a direct gene-editing approach to induce exon deletion and recover dystrophin expression in the mdx mouse model of DMD. Delivery by adeno-associated virus (AAV) of clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 endonucleases coupled with paired guide RNAs flanking the mutated Dmd exon23 resulted in excision of intervening DNA and restored the Dmd reading frame in myofibers, cardiomyocytes, and muscle stem cells after local or systemic delivery...
January 22, 2016: Science
Christopher E Nelson, Chady H Hakim, David G Ousterout, Pratiksha I Thakore, Eirik A Moreb, Ruth M Castellanos Rivera, Sarina Madhavan, Xiufang Pan, F Ann Ran, Winston X Yan, Aravind Asokan, Feng Zhang, Dongsheng Duan, Charles A Gersbach
Duchenne muscular dystrophy (DMD) is a devastating disease affecting about 1 out of 5000 male births and caused by mutations in the dystrophin gene. Genome editing has the potential to restore expression of a modified dystrophin gene from the native locus to modulate disease progression. In this study, adeno-associated virus was used to deliver the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 system to the mdx mouse model of DMD to remove the mutated exon 23 from the dystrophin gene...
January 22, 2016: Science
Chengzu Long, Leonela Amoasii, Alex A Mireault, John R McAnally, Hui Li, Efrain Sanchez-Ortiz, Samadrita Bhattacharyya, John M Shelton, Rhonda Bassel-Duby, Eric N Olson
CRISPR/Cas9-mediated genome editing holds clinical potential for treating genetic diseases, such as Duchenne muscular dystrophy (DMD), which is caused by mutations in the dystrophin gene. To correct DMD by skipping mutant dystrophin exons in postnatal muscle tissue in vivo, we used adeno-associated virus-9 (AAV9) to deliver gene-editing components to postnatal mdx mice, a model of DMD. Different modes of AAV9 delivery were systematically tested, including intraperitoneal at postnatal day 1 (P1), intramuscular at P12, and retro-orbital at P18...
January 22, 2016: Science
Daria Wojtal, Dwi U Kemaladewi, Zeenat Malam, Sarah Abdullah, Tatianna W Y Wong, Elzbieta Hyatt, Zahra Baghestani, Sergio Pereira, James Stavropoulos, Vincent Mouly, Kamel Mamchaoui, Francesco Muntoni, Thomas Voit, Hernan D Gonorazky, James J Dowling, Michael D Wilson, Roberto Mendoza-Londono, Evgueni A Ivakine, Ronald D Cohn
Clustered regularly interspaced short palindromic repeat (CRISPR) has arisen as a frontrunner for efficient genome engineering. However, the potentially broad therapeutic implications are largely unexplored. Here, to investigate the therapeutic potential of CRISPR/Cas9 in a diverse set of genetic disorders, we establish a pipeline that uses readily obtainable cells from affected individuals. We show that an adapted version of CRISPR/Cas9 increases the amount of utrophin, a known disease modifier in Duchenne muscular dystrophy (DMD)...
January 7, 2016: American Journal of Human Genetics
Li Xu, Ki Ho Park, Lixia Zhao, Jing Xu, Mona El Refaey, Yandi Gao, Hua Zhu, Jianjie Ma, Renzhi Han
Duchenne muscular dystrophy (DMD) is a degenerative muscle disease caused by genetic mutations that lead to the disruption of dystrophin in muscle fibers. There is no curative treatment for this devastating disease. Clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9) has emerged as a powerful tool for genetic manipulation and potential therapy. Here we demonstrate that CRIPSR-mediated genome editing efficiently excised a 23-kb genomic region on the X-chromosome covering the mutant exon 23 in a mouse model of DMD, and restored dystrophin expression and the dystrophin-glycoprotein complex at the sarcolemma of skeletal muscles in live mdx mice...
March 2016: Molecular Therapy: the Journal of the American Society of Gene Therapy
Yongchang Chen, Yinghui Zheng, Yu Kang, Weili Yang, Yuyu Niu, Xiangyu Guo, Zhuchi Tu, Chenyang Si, Hong Wang, Ruxiao Xing, Xiuqiong Pu, Shang-Hsun Yang, Shihua Li, Weizhi Ji, Xiao-Jiang Li
CRISPR/Cas9 has been used to genetically modify genomes in a variety of species, including non-human primates. Unfortunately, this new technology does cause mosaic mutations, and we do not yet know whether such mutations can functionally disrupt the targeted gene or cause the pathology seen in human disease. Addressing these issues is necessary if we are to generate large animal models of human diseases using CRISPR/Cas9. Here we used CRISPR/Cas9 to target the monkey dystrophin gene to create mutations that lead to Duchenne muscular dystrophy (DMD), a recessive X-linked form of muscular dystrophy...
July 1, 2015: Human Molecular Genetics
David G Ousterout, Ami M Kabadi, Pratiksha I Thakore, William H Majoros, Timothy E Reddy, Charles A Gersbach
The CRISPR/Cas9 genome-editing platform is a promising technology to correct the genetic basis of hereditary diseases. The versatility, efficiency and multiplexing capabilities of the CRISPR/Cas9 system enable a variety of otherwise challenging gene correction strategies. Here, we use the CRISPR/Cas9 system to restore the expression of the dystrophin gene in cells carrying dystrophin mutations that cause Duchenne muscular dystrophy (DMD). We design single or multiplexed sgRNAs to restore the dystrophin reading frame by targeting the mutational hotspot at exons 45-55 and introducing shifts within exons or deleting one or more exons...
2015: Nature Communications
Hongmei Lisa Li, Naoko Fujimoto, Noriko Sasakawa, Saya Shirai, Tokiko Ohkame, Tetsushi Sakuma, Michihiro Tanaka, Naoki Amano, Akira Watanabe, Hidetoshi Sakurai, Takashi Yamamoto, Shinya Yamanaka, Akitsu Hotta
Duchenne muscular dystrophy (DMD) is a severe muscle-degenerative disease caused by a mutation in the dystrophin gene. Genetic correction of patient-derived induced pluripotent stem cells (iPSCs) by TALENs or CRISPR-Cas9 holds promise for DMD gene therapy; however, the safety of such nuclease treatment must be determined. Using a unique k-mer database, we systematically identified a unique target region that reduces off-target sites. To restore the dystrophin protein, we performed three correction methods (exon skipping, frameshifting, and exon knockin) in DMD-patient-derived iPSCs, and found that exon knockin was the most effective approach...
January 13, 2015: Stem Cell Reports
Chengzu Long, John R McAnally, John M Shelton, Alex A Mireault, Rhonda Bassel-Duby, Eric N Olson
Duchenne muscular dystrophy (DMD) is an inherited X-linked disease caused by mutations in the gene encoding dystrophin, a protein required for muscle fiber integrity. DMD is characterized by progressive muscle weakness and a shortened life span, and there is no effective treatment. We used clustered regularly interspaced short palindromic repeat/Cas9 (CRISPR/Cas9)-mediated genome editing to correct the dystrophin gene (Dmd) mutation in the germ line of mdx mice, a model for DMD, and then monitored muscle structure and function...
September 5, 2014: Science
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