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News Article | May 16, 2017
Site: www.eurekalert.org

Spanish scientists at the University of Navarra and Vivet Therapeutics expect to begin the first clinical trials on patients in 2018 with the new VTX801 treatment which corrects an advanced stage of this rare disease in animals Pamplona (Spain), May 16. Scientists at the Center for Applied Medical Research (CIMA) at the University of Navarra (Spain) have designed a promising gene therapy method to treat Wilson's disease, a rare pathology caused by the lack of or malfunction of a gene. The gene therapy consists in introducing the correct version of the gene into the damaged cells by means of vehicles or vectors, generally viruses which have been modified in the laboratory to eliminate their capacity to cause disease but maintain their ability to penetrate the cells. With this promising method Dr. Gloria González Aseguinolaza, director of the Gene Therapy Program at CIMA, and her team have designed VTX801, a viral vector that corrects an advanced stage of Wilson's disease in animals. The Massachusetts Eye and Ear (MEE), a hospital associated with Harvard University, has participated in the development process of her innovative therapeutic strategy by contributing an advanced viral capsid (Anc80), the coating of the genetic material of the modified virus. This advance has been possible thanks to the CIMA agreement and exclusive license, through its foundation for applied medical research (FIMA) with the emerging French bio-technical company Vivet Therapeutics (Vivet). This company, which develops new treatments based on gene therapy for hereditary metabolic rare diseases, has raised €37.5 million in its Series A financing round from a consortium of investors led by Novartis Venture Fund and Columbus Venture Partners and including Roche Venture Fund, HealthCap, Kurma Partners and Ysios Capital. Outstanding is the fact that a project from a Spanish academic institution research center should attract so many international investors in the biotechnology sector. An injection with beneficial effects that continue for years Wilson's disease is caused by a mutation of the ATP7B gene, which is responsible for metabolizing copper. It causes this metal to accumulate in the liver and other tissues and produces hepatic and neurologic damage and potentially death. It affects one in 30,000 people worldwide. The current treatment attempts to mitigate the progress of the disease and consists of taking several pills daily for life, with great discomfort for the patient and a chronicity which implies high health care costs at a global level. "Our strategy goes to the root of the disease and tries to correct it", stated Dr. Gloria González Aseguinozala. And, "it consists in applying a single injection whose effects may last up to seven years, which is, up to now, the follow-up time of a patient treated with gene therapy". According to the researcher, the successful results in mice at an advanced stage of the disease together with the agreement with Vivet "have allowed us to optimize the VTX801 vector and its production system in order to obtain large clinical grade quantities". Once the CIMA researchers have tested the safety and effectiveness of the new drug, Vivet expects to begin the first clinical trials with VTX801 towards the end of 2018. González Aseguinozala points out that her research "has focused on Wilson's disease because it is the first for which we have satisfactory data and the possibilities of being of benefit to patients are more immediate. However, the potential of this therapeutic strategy opens the doors to other treatments with gene therapy, as, by changing the defective gene, we may be able to address diseases with a similar cause". Caption: CIMA researchers on the Vivet project. In the center, Gloria González Aseguinolaza and on the far right Jesús Hernández, a representative of FIMA and previous director general of CIMA.


ROCKVILLE, Md., May 04, 2017 (GLOBE NEWSWIRE) -- REGENXBIO Inc. (Nasdaq:RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAV® Technology Platform, today announced that preclinical data from studies supported by REGENXBIO at the University of Pennsylvania’s Gene Therapy Program and Center for Advanced Retinal and Ocular Therapeutics and at the Johns Hopkins Wilmer Eye Institute will be shared in one presentation and four posters at upcoming conferences including the Retinal Cell and Gene Therapy Innovation Summit, the Association for Research in Vision and Ophthalmology (ARVO), and the American Society of Gene and Cell Therapy (ASGCT). These data support further clinical research regarding the use of REGENXBIO’s investigational gene therapy RGX-314 for the treatment of wet age-related macular degeneration (wet AMD). “RGX-314 has the potential to be a one-time treatment for people with wet AMD by delivering high expression of anti-VEGF antibodies through the use of our NAV AAV8 vector. We are pleased to share additional positive preclinical results, which were generated by our development partners at the University of Pennsylvania and Johns Hopkins, which support our active IND,” said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. “REGENXBIO is on track to begin enrollment in the RGX-314 Phase I clinical trial by mid-2017 and to provide an interim trial update by the end of 2017.” Details of the upcoming presentation and posters are as follows: Title: Preclinical gene therapy studies to select RGX-314 doses to treat wet age-related macular degeneration Presenter: Jean Bennett, PhD, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA Session date/time: Friday, May 5, 9:20 a.m. – 9:30 a.m. EDT Session title: Gene Therapy, Outcome Measures, and Novel Therapies, Session 1: Preclinical Aspects — Vector Design/Animal Models Room: Holiday 1-3, Hilton Baltimore, Baltimore, MD Posters at Association for Research in Vision and Ophthalmology Title: RGX-314, an AAV8 expressing an anti-VEGF protein, strongly suppresses subretinal neovascularization and vascular leakage in mouse models  Authors: Ji-kui Shen1, Yuanyuan Liu1, Seth D. Fortmann1, Stephen Yoo3, Karen Kozarsky2, Jiangxia Wang1, Peter A. Campochiaro1. 1Ophthalmology, Johns Hopkins Wilmer Eye Inst, Baltimore, Maryland, United States; 3REGENXBIO Inc, Rockville, Maryland, United States Session date/time: Sunday, May 7, 8:30 a.m. – 10:15 a.m. EDT  Session title: Cytokines; Growth factors; Antiangiogenic drugs  Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0230  Title: Subretinal delivery of RGX-314 AAV8-anti-VEGF Fab gene therapy in NHP Authors: Anna Tretiakova1, Tomas S. Aleman3, Arkady Lyubarsky3, Elaine J. Zhou4, Erik Wielechowski1, Gui-Shuang Ying2, Erin Bote1, Leah Makaron1, Stephen Yoo5, Jean Bennett3,6, Albert M. Maguire3,6, James Wilson1. 1Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 4Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 5REGENXBIO, Rockville, Maryland, United States; 6Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States Session date/times: Wednesday, May 10, 11:00 a.m. – 12:45 p.m. EDT Session title: Gene editing and gene therapies Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0164 Title: Normal parameters of the full field ERG recorded with bipolar electrodes in Cynomolgus Macaque (Macaque fascicularis)  Authors: Arkady Lyubarsky1,2, Erik Wielechowski3, Tomas S. Aleman4, Albert M. Maguire1,4, Gui-Shuang Ying4, Erin Bote3, Leah Makaron3, James Wilson3, Jean Bennett1,4, Anna P. Tretiakova3. 1Center for Advanced Retinal and Ophthalmic Therapeutics, SOM Univ. of Pennsylvania, Philadelphia, Pennsylvania, United States; 2Vision Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States; 4Scheie Eye Institute, University of Pennsylvania SOM Ophthalmology, Philadelphia, Pennsylvania, United States Session date/times: Thursday, May 11, 8:30 a.m. – 10:15 a.m. EDT  Session title: Retinal Function – ERG studies  Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0441 Additional information on the meeting can be found on the ARVO website: http://www.arvo.org Poster at American Society of Gene and Cell Therapy Title: Safety of RGX-314 AAV8-anti-VEGF Fab Gene Therapy in NHP Following Subretinal Delivery Authors: Tomas S. Aleman1, Anna P. Tretiakova2, Arkady L. Lyubarsky1, Jessica I. W. Morgan2, Elaine J. Zhou3, Erik Wielechowski2, Gui-Shuang Ying4, Erin Bote2, Leah Makaron2, Stephen Yoo5, Jean Bennett1, Albert M. Maguire1, James M. Wilson2. 1Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA,2Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA,3Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,4Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA,5REGENXBIO, Rockville, MD. Session date/times: Thursday, May 11, 5:15 p.m. – 7:15 p.m. EDT Session title: Neurologic Diseases (including Ophthalmic and Auditory Diseases) II Room: Exhibit Hall A & B South, Marriot Wardham Park Hotel, Washington, DC Abstract number: 427 Additional information on the meeting can be found on the ASGCT website: http://www.asgct.org Penn has licensed certain Penn-owned AAV intellectual property to REGENXBIO, including rights related to RGX-314. Dr. Wilson is an advisor to REGENXBIO and is a founder of, holds equity in, and receives sponsored research support from REGENXBIO. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO’s NAV® Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO and its third-party NAV Technology Licensees are applying the NAV Technology Platform in the development of a broad pipeline of product candidates in multiple therapeutic areas. This press release contains “forward-looking statements,” within the meaning of the Private Securities Litigation Reform Act of 1995, regarding, among other things, REGENXBIO’s research, development and regulatory plans in connection with its NAV Technology Platform and gene therapy treatments. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could cause actual results to differ materially from those projected by such forward-looking statements. All of REGENXBIO’s development timelines could be subject to adjustment depending on recruitment rate, regulatory agency review and other factors that could delay the initiation and completion of clinical trials. Meaningful factors which could cause actual results to differ include, but are not limited to, the timing of enrollment, commencement and completion of REGENXBIO’s clinical trials; the timing and success of preclinical studies and clinical trials conducted by REGENXBIO and its development partners; the ability to obtain and maintain regulatory approval of REGENXBIO’s product candidates and the labeling for any approved products; the scope, progress, expansion, and costs of developing and commercializing REGENXBIO’s product candidates; REGENXBIO’s ability to obtain and maintain intellectual property protection for REGENXBIO’s product candidates and technology; REGENXBIO’s growth strategies; REGENXBIO’s competition; trends and challenges in REGENXBIO’s business and the markets in which REGENXBIO operates; REGENXBIO’s ability to attract or retain key personnel; the size and growth of the potential markets for REGENXBIO’s product candidates and the ability to serve those markets; the rate and degree of market acceptance of any of REGENXBIO’s product candidates; REGENXBIO’s ability to establish and maintain development partnerships; REGENXBIO’s expenses and revenue; regulatory developments in the United States and foreign countries; the sufficiency of REGENXBIO’s cash resources and needs for additional financing; and other factors discussed in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of REGENXBIO’s Annual Report on Form 10-K for the year ended December 31, 2016. In addition to the risks described above and in REGENXBIO’s filings with the Securities and Exchange Commission, other unknown or unpredictable factors also could affect REGENXBIO’s results. There can be no assurance that the actual results or developments anticipated by REGENXBIO will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, REGENXBIO. Therefore, no assurance can be given that the outcomes stated in such forward-looking statements and estimates will be achieved. All forward-looking statements contained in this press release are expressly qualified by the cautionary statements contained or referred to herein. REGENXBIO cautions investors not to rely too heavily on the forward-looking statements REGENXBIO makes or that are made on its behalf. These forward-looking statements speak only as of the date of this press release (unless another date is indicated). REGENXBIO undertakes no obligation, and specifically declines any obligation, to publicly update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.


ROCKVILLE, Md., May 04, 2017 (GLOBE NEWSWIRE) -- REGENXBIO Inc. (Nasdaq:RGNX), a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy based on its proprietary NAV® Technology Platform, today announced that preclinical data from studies supported by REGENXBIO at the University of Pennsylvania’s Gene Therapy Program and Center for Advanced Retinal and Ocular Therapeutics and at the Johns Hopkins Wilmer Eye Institute will be shared in one presentation and four posters at upcoming conferences including the Retinal Cell and Gene Therapy Innovation Summit, the Association for Research in Vision and Ophthalmology (ARVO), and the American Society of Gene and Cell Therapy (ASGCT). These data support further clinical research regarding the use of REGENXBIO’s investigational gene therapy RGX-314 for the treatment of wet age-related macular degeneration (wet AMD). “RGX-314 has the potential to be a one-time treatment for people with wet AMD by delivering high expression of anti-VEGF antibodies through the use of our NAV AAV8 vector. We are pleased to share additional positive preclinical results, which were generated by our development partners at the University of Pennsylvania and Johns Hopkins, which support our active IND,” said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. “REGENXBIO is on track to begin enrollment in the RGX-314 Phase I clinical trial by mid-2017 and to provide an interim trial update by the end of 2017.” Details of the upcoming presentation and posters are as follows: Title: Preclinical gene therapy studies to select RGX-314 doses to treat wet age-related macular degeneration Presenter: Jean Bennett, PhD, Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA Session date/time: Friday, May 5, 9:20 a.m. – 9:30 a.m. EDT Session title: Gene Therapy, Outcome Measures, and Novel Therapies, Session 1: Preclinical Aspects — Vector Design/Animal Models Room: Holiday 1-3, Hilton Baltimore, Baltimore, MD Posters at Association for Research in Vision and Ophthalmology Title: RGX-314, an AAV8 expressing an anti-VEGF protein, strongly suppresses subretinal neovascularization and vascular leakage in mouse models  Authors: Ji-kui Shen1, Yuanyuan Liu1, Seth D. Fortmann1, Stephen Yoo3, Karen Kozarsky2, Jiangxia Wang1, Peter A. Campochiaro1. 1Ophthalmology, Johns Hopkins Wilmer Eye Inst, Baltimore, Maryland, United States; 3REGENXBIO Inc, Rockville, Maryland, United States Session date/time: Sunday, May 7, 8:30 a.m. – 10:15 a.m. EDT  Session title: Cytokines; Growth factors; Antiangiogenic drugs  Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0230  Title: Subretinal delivery of RGX-314 AAV8-anti-VEGF Fab gene therapy in NHP Authors: Anna Tretiakova1, Tomas S. Aleman3, Arkady Lyubarsky3, Elaine J. Zhou4, Erik Wielechowski1, Gui-Shuang Ying2, Erin Bote1, Leah Makaron1, Stephen Yoo5, Jean Bennett3,6, Albert M. Maguire3,6, James Wilson1. 1Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 2Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 4Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 5REGENXBIO, Rockville, Maryland, United States; 6Center for Cellular and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States Session date/times: Wednesday, May 10, 11:00 a.m. – 12:45 p.m. EDT Session title: Gene editing and gene therapies Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0164 Title: Normal parameters of the full field ERG recorded with bipolar electrodes in Cynomolgus Macaque (Macaque fascicularis)  Authors: Arkady Lyubarsky1,2, Erik Wielechowski3, Tomas S. Aleman4, Albert M. Maguire1,4, Gui-Shuang Ying4, Erin Bote3, Leah Makaron3, James Wilson3, Jean Bennett1,4, Anna P. Tretiakova3. 1Center for Advanced Retinal and Ophthalmic Therapeutics, SOM Univ. of Pennsylvania, Philadelphia, Pennsylvania, United States; 2Vision Research Center, University of Pennsylvania, Philadelphia, Pennsylvania, United States; 3Gene Therapy Program, University of Pennsylvania SOM, Philadelphia, Pennsylvania, United States; 4Scheie Eye Institute, University of Pennsylvania SOM Ophthalmology, Philadelphia, Pennsylvania, United States Session date/times: Thursday, May 11, 8:30 a.m. – 10:15 a.m. EDT  Session title: Retinal Function – ERG studies  Room: Exhibit/Poster Hall, Baltimore Convention Center, Baltimore, MD Abstract number: B0441 Additional information on the meeting can be found on the ARVO website: http://www.arvo.org Poster at American Society of Gene and Cell Therapy Title: Safety of RGX-314 AAV8-anti-VEGF Fab Gene Therapy in NHP Following Subretinal Delivery Authors: Tomas S. Aleman1, Anna P. Tretiakova2, Arkady L. Lyubarsky1, Jessica I. W. Morgan2, Elaine J. Zhou3, Erik Wielechowski2, Gui-Shuang Ying4, Erin Bote2, Leah Makaron2, Stephen Yoo5, Jean Bennett1, Albert M. Maguire1, James M. Wilson2. 1Center for Advanced Retinal and Ocular Therapeutics, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA,2Gene Therapy Program, Department of Medicine, University of Pennsylvania, Philadelphia, PA,3Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA,4Center for Preventative Ophthalmology and Biostatistics, University of Pennsylvania, Philadelphia, PA,5REGENXBIO, Rockville, MD. Session date/times: Thursday, May 11, 5:15 p.m. – 7:15 p.m. EDT Session title: Neurologic Diseases (including Ophthalmic and Auditory Diseases) II Room: Exhibit Hall A & B South, Marriot Wardham Park Hotel, Washington, DC Abstract number: 427 Additional information on the meeting can be found on the ASGCT website: http://www.asgct.org Penn has licensed certain Penn-owned AAV intellectual property to REGENXBIO, including rights related to RGX-314. Dr. Wilson is an advisor to REGENXBIO and is a founder of, holds equity in, and receives sponsored research support from REGENXBIO. REGENXBIO is a leading clinical-stage biotechnology company seeking to improve lives through the curative potential of gene therapy. REGENXBIO’s NAV® Technology Platform, a proprietary adeno-associated virus (AAV) gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO and its third-party NAV Technology Licensees are applying the NAV Technology Platform in the development of a broad pipeline of product candidates in multiple therapeutic areas. This press release contains “forward-looking statements,” within the meaning of the Private Securities Litigation Reform Act of 1995, regarding, among other things, REGENXBIO’s research, development and regulatory plans in connection with its NAV Technology Platform and gene therapy treatments. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could cause actual results to differ materially from those projected by such forward-looking statements. All of REGENXBIO’s development timelines could be subject to adjustment depending on recruitment rate, regulatory agency review and other factors that could delay the initiation and completion of clinical trials. Meaningful factors which could cause actual results to differ include, but are not limited to, the timing of enrollment, commencement and completion of REGENXBIO’s clinical trials; the timing and success of preclinical studies and clinical trials conducted by REGENXBIO and its development partners; the ability to obtain and maintain regulatory approval of REGENXBIO’s product candidates and the labeling for any approved products; the scope, progress, expansion, and costs of developing and commercializing REGENXBIO’s product candidates; REGENXBIO’s ability to obtain and maintain intellectual property protection for REGENXBIO’s product candidates and technology; REGENXBIO’s growth strategies; REGENXBIO’s competition; trends and challenges in REGENXBIO’s business and the markets in which REGENXBIO operates; REGENXBIO’s ability to attract or retain key personnel; the size and growth of the potential markets for REGENXBIO’s product candidates and the ability to serve those markets; the rate and degree of market acceptance of any of REGENXBIO’s product candidates; REGENXBIO’s ability to establish and maintain development partnerships; REGENXBIO’s expenses and revenue; regulatory developments in the United States and foreign countries; the sufficiency of REGENXBIO’s cash resources and needs for additional financing; and other factors discussed in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of REGENXBIO’s Annual Report on Form 10-K for the year ended December 31, 2016. In addition to the risks described above and in REGENXBIO’s filings with the Securities and Exchange Commission, other unknown or unpredictable factors also could affect REGENXBIO’s results. There can be no assurance that the actual results or developments anticipated by REGENXBIO will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, REGENXBIO. Therefore, no assurance can be given that the outcomes stated in such forward-looking statements and estimates will be achieved. All forward-looking statements contained in this press release are expressly qualified by the cautionary statements contained or referred to herein. REGENXBIO cautions investors not to rely too heavily on the forward-looking statements REGENXBIO makes or that are made on its behalf. These forward-looking statements speak only as of the date of this press release (unless another date is indicated). REGENXBIO undertakes no obligation, and specifically declines any obligation, to publicly update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.


News Article | November 30, 2016
Site: www.eurekalert.org

(PHILADELPHIA) - CRISPR/Cas9, a powerful genome editing tool, is showing promise for efficient correction of disease-causing mutations. For the first time, researchers from the Perelman School of Medicine at the University of Pennsylvania have developed a dual gene therapy approach to deliver key components of a CRISPR/Cas9-mediated gene targeting system to mice to treat hemophilia B. This disorder is also called factor IX deficiency and is caused by a missing or defective clotting protein. Their research will be presented during the 58th Annual American Society of Hematology Meeting and Exposition in San Diego from December 3-6 (Abstract #1174). Most single-gene diseases, such as hemophilia, are caused by different mutations scattered in a specific gene rather than a single predominant mutation, so the team needed to develop a vector that would be applicable for patients with any mutations. The study is a preclinical proof of concept using a universal CRISPR/Cas9 gene targeting approach that could be applied to majority of the patients with a specific disease, in this case hemophilia B. According to the Centers for Disease Control and Prevention, hemophilia in general occurs in approximately 1 in 5,000 live births and there are about 20,000 people with hemophilia in the United States. "Basically, we cured the mice," said first author Lili Wang, PhD, a research associate professor in the Penn Gene Therapy Program (GTP). James M Wilson, MD, PhD, a professor of medicine and GTP director, is senior author on the study. To validate this new approach, the team performed the experiment in a mouse model in which the clotting factor IX was knocked out. They used a two-vector approach, with vector 1 expressing the SaCas9 gene driven by a liver-specific promoter so that the gene-editing machinery homes to the liver, the natural site that produces clotting factor IX. Vector 2 is what makes this study different from previous CRISPR-based-gene-therapy studies in the Penn Gene Therapy Program. Vector 2 contains an RNA sequence that specifically targets a region at the 5-prime end of exon 2 of the mouse factor IX gene and a partial human factor IX cDNA sequence, which gives this approach more potency and accuracy. The team used adeno-associated viral vectors to deliver these components to the mouse liver cells. The strategy they developed is based on CRISPR-mediated homologous recombination to insert the human cDNA into the factor IX location on the mouse genome. "The targeted insertion leads to the expression of a chimeric hyperactive factor IX protein under the control of the native mouse factor IX promoter," Wang said. Injection of the two vectors with increasing doses in newborn and adult knockout mice showed stable Factor IX activity at or above the normal levels over four months. Eight weeks after the vector treatment, a subgroup of the newborn and adult treated knockout mice were given a partial liver removal and all of them survived the procedure without any complications or interventions and continued to express factor IX at similar levels. "This study provides convincing evidence for efficacy in a hemophilia B mouse model following in vivo genome editing by CRISPR/Cas9," Wang said. Yang Yang PhD, a visiting scientist in the Wilson lab, and John White, McMenamin Deirdre, and Peter Bell, PhD, all from Penn, are also coauthors. This research was supported by the Orphan Disease Center at Penn. For more Penn Medicine news from the 58th Annual American Society of Hematology Meeting, visit: http://www. Penn Medicine is one of the world's leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the Raymond and Ruth Perelman School of Medicine at the University of Pennsylvania (founded in 1765 as the nation's first medical school) and the University of Pennsylvania Health System, which together form a $5.3 billion enterprise. The Perelman School of Medicine has been ranked among the top five medical schools in the United States for the past 18 years, according to U.S. News & World Report's survey of research-oriented medical schools. The School is consistently among the nation's top recipients of funding from the National Institutes of Health, with $373 million awarded in the 2015 fiscal year. The University of Pennsylvania Health System's patient care facilities include: The Hospital of the University of Pennsylvania and Penn Presbyterian Medical Center -- which are recognized as one of the nation's top "Honor Roll" hospitals by U.S. News & World Report -- Chester County Hospital; Lancaster General Health; Penn Wissahickon Hospice; and Pennsylvania Hospital -- the nation's first hospital, founded in 1751. Additional affiliated inpatient care facilities and services throughout the Philadelphia region include Chestnut Hill Hospital and Good Shepherd Penn Partners, a partnership between Good Shepherd Rehabilitation Network and Penn Medicine. Penn Medicine is committed to improving lives and health through a variety of community-based programs and activities. In fiscal year 2015, Penn Medicine provided $253.3 million to benefit our community.


News Article | November 30, 2016
Site: www.chromatographytechniques.com

CRISPR/Cas9, a powerful genome editing tool, is showing promise for efficient correction of disease-causing mutations. For the first time, researchers from the Perelman School of Medicine at the University of Pennsylvania have developed a dual gene therapy approach to deliver key components of a CRISPR/Cas9-mediated gene targeting system to mice to treat hemophilia B. This disorder is also called factor IX deficiency and is caused by a missing or defective clotting protein. Their research will be presented during the 58th Annual American Society of Hematology Meeting and Exposition in San Diego from December 3rd to 6th. Most single-gene diseases, such as hemophilia, are caused by different mutations scattered in a specific gene rather than a single predominant mutation, so the team needed to develop a vector that would be applicable for patients with any mutations. The study is a preclinical proof of concept using a universal CRISPR/Cas9 gene targeting approach that could be applied to majority of the patients with a specific disease, in this case hemophilia B. According to the Centers for Disease Control and Prevention, hemophilia in general occurs in approximately one in 5,000 live births and there are about 20,000 people with hemophilia in the United States. "Basically, we cured the mice," said first author Lili Wang, PhD, a research associate professor in the Penn Gene Therapy Program (GTP). James M Wilson, MD, PhD, a professor of medicine and GTP director, is senior author on the study. To validate this new approach, the team performed the experiment in a mouse model in which the clotting factor IX was knocked out. They used a two-vector approach, with vector 1 expressing the SaCas9 gene driven by a liver-specific promoter so that the gene-editing machinery homes to the liver, the natural site that produces clotting factor IX. Vector 2 is what makes this study different from previous CRISPR-based-gene-therapy studies in the Penn Gene Therapy Program. Vector 2 contains an RNA sequence that specifically targets a region at the 5-prime end of exon 2 of the mouse factor IX gene and a partial human factor IX cDNA sequence, which gives this approach more potency and accuracy. The team used adeno-associated viral vectors to deliver these components to the mouse liver cells. The strategy they developed is based on CRISPR-mediated homologous recombination to insert the human cDNA into the factor IX location on the mouse genome. "The targeted insertion leads to the expression of a chimeric hyperactive factor IX protein under the control of the native mouse factor IX promoter," Wang said. Injection of the two vectors with increasing doses in newborn and adult knockout mice showed stable Factor IX activity at or above the normal levels over four months. Eight weeks after the vector treatment, a subgroup of the newborn and adult treated knockout mice were given a partial liver removal and all of them survived the procedure without any complications or interventions and continued to express factor IX at similar levels. "This study provides convincing evidence for efficacy in a hemophilia B mouse model following in vivo genome editing by CRISPR/Cas9," Wang said. Yang Yang PhD, a visiting scientist in the Wilson lab, and John White, McMenamin Deirdre, and Peter Bell, PhD, all from Penn, are also coauthors.


News Article | December 2, 2016
Site: www.techtimes.com

Ticked Off! Here's What You Need To Know About Lyme Disease A dual gene therapy approach was employed for the first time in delivering key components of a CRISPR/Cas-9 mediated gene targeting system that would help treat hemophilia B. The research was conducted on mice, and it addressed the disease that is also called factor IX deficiency. The study, conducted by scientists at the Perelman School of Medicine at the University of Pennsylvania, tried to treat the illness triggered by a missing or defective clotting protein. "Basically, we cured the mice," noted Lili Wang, Ph.D., research associate professor in the Penn Gene Therapy Program. The researchers experimented on a mouse model where the clotting factor IX was knocked out in order to cure hemophilia. The team employed a two-vector method. Vector 1 expressed the SaCas9 gene for the gene-editing system to home to the liver, thus producing the clotting factor IX. Vector 2 is where this study is different from previous ones conducted as part of the same program; it contains an RNA sequence which targets a specific region, making the approach more accurate in curing hemophilia. The researchers injected the two vectors with progressively increasing doses in newborn and adult knockout mice. The results were a stable factor IX activity. Eight weeks after administrating the treatment, the researchers created a subgroup of the mice category, who were also administered a partial liver removal. All the mice survived the medical procedure, and no complications followed this medical approach. While the current research brings a new approach that could help treat this rare genetic disorder, other steps have been made in this direction in the recent years, in order for patients who suffer from this disease to lead better lives. Back in 2014, the Food and Drug Administration approved a treatment that was considered the first recombinant, DNA-derived therapy for the rare disorder. "The approval of this product provides another therapeutic option for the treatment and prevention of bleeding in patients with Hemophilia B," noted Dr. Karen Midthun, FDA's Center for Biologics Evaluation and Research director, when the treatment was approved. Due to the fact that people who suffer from this affection lack factor IX, the most common symptom is prolonged oozing after injuries, as well as tooth extractions or surgery. The delayed or recurrent bleeding is also a symptom associated with this disease; depending on the stage of the disease, the symptoms can be more severe or scarce. "In any individual with hemophilia B, bleeding episodes may be more frequent in childhood and adolescence than in adulthood," according to the National Center of Biotechnology Information. © 2017 Tech Times, All rights reserved. Do not reproduce without permission.


ROCKVILLE, Md., Feb. 14, 2017 (GLOBE NEWSWIRE) -- REGENXBIO Inc. (Nasdaq:RGNX), a leading biotechnology company focused on the development, commercialization and licensing of recombinant adeno-associated virus (AAV) gene therapy based on its proprietary NAV® Technology Platform, today announced the Investigational New Drug application (IND) is active for the planned multi-center, open-label, multiple-cohort, dose-escalation Phase I clinical trial of RGX-314 for the treatment of wet age-related macular degeneration (wet AMD). “The goal of the RGX-314 program is to develop a single-dose treatment for wet AMD that prevents future disease recurrence while reducing or eliminating the need for regular injections that are the current standard of care in wet AMD,” said Kenneth T. Mills, President and Chief Executive Officer of REGENXBIO. “We are on track to meet our next program objectives for RGX-314, beginning with trial enrollment by mid-2017 and an interim trial update by the end of the year, and we look forward to working with leading U.S. researchers and retina surgeons on this novel clinical program.” RGX-314 is being developed under a multi-institutional collaboration with world-renowned gene therapy and ophthalmology experts James M. Wilson, M.D., Ph.D., Jean Bennett, M.D., Ph.D. and Albert Maguire, M.D. from the University of Pennsylvania’s Gene Therapy Program and Center for Advanced Retinal and Ocular Therapeutics (Penn), respectively, and Peter Campochiaro, M.D. at the Johns Hopkins Wilmer Eye Institute (Johns Hopkins). “In animal studies, treatment with RGX-314 gene therapy led to rapid and sustained anti-VEGF protein detected in the eyes of treated animals. Preclinical studies have shown anti-VEGF mRNA and protein distributed widely throughout the retina. This high protein expression observed using RGX-314’s NAV AAV8 vector may make this approach suitable for an ocular therapeutic in wet AMD,” said Dr. Maguire. Six leading retinal surgery centers across the United States, including Penn and Johns Hopkins, are expected to participate in the Phase I trial of RGX-314. About the Phase I Clinical Trial of RGX-314 RGX‑314 will be evaluated in a Phase I, multi-center, open-label, multiple-cohort, dose‑escalation study in adult subjects with wet AMD in the United States. The study is expected to include approximately eighteen previously treated wet AMD subjects that are responsive to anti-vascular endothelial growth factor (anti-VEGF) therapy and are 50 years of age or older. The study is designed to evaluate three doses of RGX-314 (3 × 10^9 genome copies (GC)/eye, 1 × 10^10 GC/eye, and 6 × 10^10 GC/eye). Primary endpoints include adverse events, certain laboratory measures (including immunological parameters) and ocular examinations and imaging (including BCVA and SD‑OCT). The primary purpose of the clinical study is to evaluate the safety and tolerability of RGX-314 at 24 weeks after a single dose of RGX-314 administered by subretinal delivery. Following completion of the primary study period, it is expected that subjects will enter the follow-up period and will continue to be assessed until week 106 to assess long term safety and durability of effect. Wet AMD is characterized by loss of vision due to excess blood vessel formation between two layers of cells in the retina, which results in fluid leakage that can result in physical changes in the structure of the retina and changes in vision. Wet AMD is a leading cause of total and partial vision loss in the United States, Europe and Japan and there may be over two million individuals living with wet AMD in these geographies alone. Current anti-VEGF therapies have significantly changed the landscape for treatment of wet AMD, becoming the standard of care due to their ability to halt or significantly impede the loss of vision in the majority of patients with wet AMD. All of these therapies, however, require repetitive and inconvenient intraocular injections, typically ranging from every four to eight weeks in frequency, to maintain efficacy. Patients often experience vision loss with reduced frequency of treatment. RGX-314 is being developed as a novel, one-time subretinal treatment for wet AMD that includes the NAV AAV8 vector encoding a gene for a monoclonal antibody fragment. The expressed protein is designed to neutralize VEGF activity, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation. In preclinical animal models with conditions similar to macular degeneration, significant and dose-dependent reduction of blood vessel growth and prevention of disease progression was observed after a single subretinal dose of RGX-314. REGENXBIO is a leading biotechnology company focused on the development, commercialization and licensing of recombinant adeno-associated virus (AAV) gene therapy. REGENXBIO’s NAV® Technology Platform, a proprietary AAV gene delivery platform, consists of exclusive rights to more than 100 novel AAV vectors, including AAV7, AAV8, AAV9 and AAVrh10. REGENXBIO’s mission is to transform the lives of patients suffering from severe diseases with significant unmet medical need by developing and commercializing in vivo gene therapy products based on REGENXBIO’s NAV Technology Platform. REGENXBIO seeks to accomplish this mission through a combination of internal development efforts and third-party NAV Technology Platform Licensees. REGENXBIO and its licensees are applying the NAV Technology Platform in the development of a broad pipeline of candidates in multiple therapeutic areas. Penn has licensed certain Penn-owned AAV technologies to REGENXBIO, including rights related to RGX-314. Dr. Wilson is an advisor to REGENXBIO, and is a founder of, holds equity in, and receives grants from REGENXBIO. This press release contains “forward-looking statements,” within the meaning of the Private Securities Litigation Reform Act of 1995, regarding, among other things, REGENXBIO’s research, development and regulatory plans and objectives for its RGX-314 program, including REGENXBIO’s Phase I clinical trial of RGX-314. Such forward-looking statements are based on current expectations and involve inherent risks and uncertainties, including factors that could cause actual results to differ materially from those projected by such forward-looking statements. All of REGENXBIO’s development timelines, including for RGX-314, could be subject to adjustment depending on recruitment rate, regulatory agency review and other factors that could delay the initiation and completion of clinical trials. Meaningful factors which could cause actual results to differ include, but are not limited to, the timing of enrollment, commencement and completion of REGENXBIO’s clinical trials; the timing and success of preclinical studies and clinical trials conducted by REGENXBIO and its development partners; the ability to obtain and maintain regulatory approval to conduct clinical trials and to commercialize REGENXBIO’s product candidates, the labeling for any approved products; the scope, progress, expansion, and costs of developing and commercializing REGENXBIO’s product candidates; competitive products; REGENXBIO’s ability to obtain and maintain intellectual property protection for REGENXBIO’s product candidates and technology; trends and challenges in REGENXBIO’s business and the markets in which REGENXBIO operates; REGENXBIO’s ability to attract or retain key personnel; the size and growth of the potential markets for REGENXBIO’s product candidates and the ability to serve those markets; the rate and degree of market acceptance of any of REGENXBIO’s product candidates; REGENXBIO’s ability to establish and maintain development partnerships; REGENXBIO’s expenses and revenue, the sufficiency of REGENXBIO’s cash resources and needs for additional financing, regulatory developments in the United States and foreign countries, as well as other factors discussed in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of REGENXBIO’s Annual Report on Form 10-K for the year ended December 31, 2015 and Quarterly Report on Form 10-Q for the quarter ended September 30, 2016, which are available on the SEC’s website at www.sec.gov. Additional factors may be set forth in those sections of REGENXBIO’s Annual Report on Form 10-K for the year ended December 31, 2016, to be filed in the first quarter of 2017. In addition to the risks described above and in REGENXBIO’s filings with the SEC, other unknown or unpredictable factors also could affect REGENXBIO’s results. There can be no assurance that the actual results or developments anticipated by REGENXBIO will be realized or, even if substantially realized, that they will have the expected consequences to, or effects on, REGENXBIO. Therefore, no assurance can be given that the outcomes stated in such forward-looking statements and estimates will be achieved. All forward-looking statements contained in this press release are expressly qualified by the cautionary statements contained or referred to herein. REGENXBIO cautions investors not to rely too heavily on the forward-looking statements REGENXBIO makes or that are made on its behalf. These forward-looking statements speak only as of the date of this press release (unless another date is indicated). REGENXBIO undertakes no obligation, and specifically declines any obligation, to publicly update or revise any such forward-looking statements, whether as a result of new information, future events or otherwise.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--Sarepta Therapeutics, Inc. (NASDAQ:SRPT), a commercial-stage biopharmaceutical company focused on the discovery and development of unique RNA-targeted therapeutics for the treatment of rare neuromuscular diseases, today reported financial results for the three and twelve months ended December 31, 2016. “2016 was a transformative year, with the FDA accelerated approval of EXONDYS 51. In 2017, we are focused on our strategy to build shareholder value by executing a successful launch of EXONDYS 51 in the US, reaching more patients through global expansion, and rapidly advancing our pipeline through internal and external development efforts,” said Edward Kaye, Sarepta’s chief executive officer. “We are pleased with the interest from the patient and physician community for EXONDYS 51, and with the progress we have made in discussions with payers. We believe this positions us well for potential growth and towards our goal at Sarepta Therapeutics to help all boys with Duchenne muscular dystrophy.” For the fourth quarter of 2016, Sarepta reported a net loss of $88.5 million, or $1.62 per share, compared to a net loss of $64.7 million for the same period of 2015, or $1.44 per share. The incremental loss of $23.8 million was primarily driven by expense recorded in connection with an up-front payment of $40.0 million related to an exclusive license agreement with Summit Therapeutics plc. (“Summit”) offset by lower manufacturing expenses that were previously captured as research and development expenses, which are now capitalized as inventory because of the approval of EXONDYS 51 by the Food and Drug Administration (“FDA”). Non-GAAP net loss for the fourth quarter of 2016 was $38.7 million, or $0.71 per share, compared to a non-GAAP net loss of $58.3 million for the fourth quarter of 2015, or $1.30 per share. The reduction of $19.7 million in Non-GAAP net loss was primarily driven by the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. For the year ended December 31, 2016, Sarepta reported a net loss of $267.3 million, or $5.49 per share, compared to a net loss of $220.0 million for the prior year, or $5.20 per share. The incremental loss of $47.2 million was primarily driven by $47.9 million of research and development expenses recorded in connection with up-front license and milestone payments related to certain license and collaboration agreements and increased costs for our on-going clinical trials primarily due to increased patient enrollment, partially offset by lower manufacturing expenses because of the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. Non-GAAP net loss for the year ended December 31, 2016 was $192.0 million, or $3.94 per share, compared to a non-GAAP net loss of $187.9 million for the prior year, or $4.44 per share. The incremental loss of $4.0 million was primarily driven by increased costs for our on-going clinical trials primarily due to increased patient enrollment partially offset by lower manufacturing expenses because of the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. The Company commenced shipments of EXONDYS 51 to customers at the end of the third quarter of 2016 following the accelerated approval by the FDA on September 19, 2016. For both the fourth quarter and full-year of 2016, the Company recognized net revenues of $5.4 million. For the same periods of 2015, the Company recognized $1.3 million of revenue from the contract finalization of the Ebola portion of the July 2010 Department of Defense contract. Research and development expenses were $70.7 million for the fourth quarter of 2016, compared to $41.4 million for the same period of 2015, an increase of $29.4 million, which was primarily driven by expense recorded in connection with an up-front payment of $40.0 million related to the exclusive license agreement with Summit offset by lower manufacturing expenses because of the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. Non-GAAP research and development expenses were $27.8 million for the fourth quarter of 2016, compared to $38.6 million for the same period of 2015, a decrease of $10.8 million, which was primarily driven by lower manufacturing expense because of the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. Research and development expenses were $188.3 million for the year ended December 31, 2016, compared to $146.4 million for the prior year, an increase of $41.9 million, which was primarily driven by $47.9 million of expenses recorded in connection with up-front license and milestone payments related to certain license and collaboration agreements and increased clinical trial costs, partially offset by lower manufacturing expenses because of the capitalization of inventory upon the approval of EXONDYS 51 by the FDA. Non-GAAP research and development expenses were $136.0 million for both the year ended December 31, 2016, and the prior year. Selling, general and administrative expenses were $22.9 million for the fourth quarter of 2016, compared to $24.3 million for the same period of 2015, a decrease of $1.4 million, which was primarily driven by decreased external professional services due to lower litigation activities partially offset by increases in restructuring expense and stock-based compensation expense. Non-GAAP selling, general and administrative expenses were $16.1 million for the fourth quarter of 2016, compared to $20.7 million for the same period of 2015, a decrease of $4.6 million, which was primarily driven by decreased external professional fees due to lower litigation activities. Selling, general and administrative expenses for the year ended December 31, 2016 were $83.7 million, compared to $75.0 million for the prior year, an increase of $8.7 million, which was primarily driven by increases in compensation expenses due to increases in commercial headcount and restructuring expenses offset by decreases in severance expense related to the resignation of our former CEO in March 2015 and professional services primarily due to lower litigation activities. Non-GAAP selling, general and administrative expenses were $60.7 million for the year ended December 31, 2016, compared to $53.3 million for the same period of 2015, an increase of $7.4 million, which was primarily driven by increase in compensation expenses due to increased commercial headcount offset by decreased external professional fees due to lower litigation activities. The Company had $329.3 million in cash, cash equivalents and restricted cash and investments as of December 31, 2016 compared to $204.0 million as of December 31, 2015, an increase of $125.4 million. The increase was driven by the net proceeds received from the Company’s public offerings in June and September 2016, offset by the use of cash to fund the Company’s ongoing operations. In addition to the GAAP financial measures set forth in this press release, the Company has included certain non-GAAP measurements: non-GAAP research and development expenses, non-GAAP selling, general and administrative expenses, non-GAAP operating expense adjustments, non-GAAP net loss, and non-GAAP basic and diluted net loss per share, which present operating results on a basis adjusted for stock-based compensation and restructuring expenses and other items. Stock-based compensation expenses represent non-cash charges related to equity awards granted by Sarepta. Although these are recurring charges to operations, management believes the measurement of these amounts can vary substantially from period to period and depend significantly on factors that are not a direct consequence of operating performance that is within management's control. Therefore, management believes that excluding these charges from non-GAAP research and development expenses, non-GAAP selling, general and administrative expenses, non-GAAP net loss and non-GAAP net loss per share facilitates comparisons of the Company’s operational performance in different periods. Restructuring expenses have been excluded from non-GAAP research and development expenses, non-GAAP selling, general and administrative expenses, non-GAAP net loss and non-GAAP net loss per share as the Company believes that the adjustments for these items represent more closely the sustainability of the Company’s operating performance and financial results. Management evaluates other items of expense and income on an individual basis. It takes into consideration quantitative and qualitative characteristics of each item, including (a) nature, (b) whether the items relates to the Company’s ongoing business operations, and (c) whether the Company expects the items to continue on a regular basis. These other items include the up-front and options payments related to existing collaboration and option agreements. The Company uses these non-GAAP measures as key performance measures for the purpose of evaluating operational performance and cash requirements internally. The Company also believes these non-GAAP measures increase comparability of period-to-period results and are useful to investors as they provide a similar basis for evaluating the Company’s performance as is applied by management. These non-GAAP measures are not intended to be considered in isolation or to replace the presentation of the Company’s financial results in accordance with GAAP. Use of the terms non-GAAP research and development expenses, non-GAAP selling, general and administrative expenses, non-GAAP operating expense adjustments, non-GAAP net loss, and non-GAAP basic and diluted net loss per share may differ from similar measures reported by other companies, which may limit comparability, and are not based on any comprehensive set of accounting rules or principles. All relevant non-GAAP measures are reconciled from their respective GAAP measures in the attached table "Reconciliation of GAAP to Non-GAAP Net Loss." -Sarepta Therapeutics Agrees to Sale of Priority Review Voucher for $125M -Sarepta Therapeutics Enters into Research Agreement and Option Agreement with Nationwide Children’s Hospital for Microdystrophin Gene Therapy Program -Sarepta Therapeutics Enters into License Agreement with Nationwide Children’s Hospital for Galgt2 Gene Therapy Program -Sarepta Therapeutics Announces EMA Validation of Eteplirsen Authorization Application for Treatment of Duchenne Muscular Dystrophy Amenable to Exon Skipping 51 Sarepta Therapeutics is a commercial-stage biopharmaceutical company focused on the discovery and development of unique RNA-targeted therapeutics for the treatment of rare neuromuscular diseases. The Company is primarily focused on rapidly advancing the development of its potentially disease-modifying Duchenne muscular dystrophy drug candidates. For more information, please visit us at www.sarepta.com. In order to provide Sarepta’s investors with an understanding of its current results and future prospects, this press release contains statements that are forward-looking. Any statements contained in this press release that are not statements of historical fact may be deemed to be forward-looking statements. Words such as “believes,” “anticipates,” “plans,” “expects,” “will,” “may,” “intends,” “prepares,” “looks,” “potential,” “possible” and similar expressions are intended to identify forward-looking statements. These forward-looking statements include statements relating to Sarepta’s future operations, financial performance and projections, business plans, priorities and development of product candidates including: Sarepta’s plans for 2017, including executing a successful launch of EXONDYS 51 in the US, reaching more patients through global expansion and rapidly advancing Sarepta’s pipeline through internal and external development efforts, and Sarepta’s belief that it is well positioned for potential growth and towards its goal to help all boys with Duchenne muscular dystrophy. These forward-looking statements involve risks and uncertainties, many of which are beyond Sarepta’s control. Actual results could materially differ from those stated or implied by these forward-looking statements as a result of such risks and uncertainties. Known risk factors include the following: we may not be able to meet expectations with respect to EXONDYS 51 sales or attain profitability and positive cash-flow from operations; we may not be able to comply with all FDA post-approval commitments and requirements with respect to EXONDYS 51 in a timely manner or at all; we may not be able to complete clinical trials required by the FDA for approval of our product candidates; the results of our ongoing research and development efforts and clinical trials for our product candidates may not be positive or consistent with prior results or demonstrate a safe treatment benefit; we may not be able to execute on our business plans, including meeting our expected or planned regulatory milestones and timelines, clinical development plans, bringing EXONDYS 51 to markets outside the United States and bringing our product candidates to market, for various reasons including possible limitations of Company financial and other resources, manufacturing limitations that may not be anticipated or resolved for in a timely manner, and regulatory, court or agency decisions, such as decisions by the United States Patent and Trademark Office with respect to patents that cover our product candidates; and those risks identified under the heading “Risk Factors” in Sarepta’s most recent Annual Report on Form 10-K for the year ended December 31, 2016 or Quarterly Reports on Form 10-Q filed with the Securities and Exchange Commission (SEC) as well as other SEC filings made by the Company which you are encouraged to review. Any of the foregoing risks could materially and adversely affect the Company’s business, results of operations and the trading price of Sarepta’s common stock. You should not place undue reliance on forward-looking statements. Sarepta does not undertake any obligation to publicly update its forward-looking statements based on events or circumstances after the date hereof, except to the extent required by applicable law or SEC rules. We routinely post information that may be important to investors in the 'For Investors' section of our web site at www.sarepta.com. We encourage investors and potential investors to consult our website regularly for important information about us.


News Article | February 1, 2016
Site: phys.org

"Correcting a disease-causing mutation following birth in this animal model brings us one step closer to realizing the potential of personalized medicine," said senior author James Wilson, MD, PhD, a professor of Medicine and director of the Orphan Disease Center at Penn. "Nevertheless, my 35-year career in gene therapy has taught me how difficult translating mouse studies to successful human treatments can be. From this study, we are now adjusting the gene-editing system in the next phases of our investigation to address the unforeseen complications seen in adult animals." Wilson is also director of the Penn Gene Therapy Program. The Wilson lab focused on liver as a target for gene editing since they had solved the problem of gene delivery in this organ in previous work using traditional gene therapy using vectors based on adeno-associated virus (AAV). However, gene replacement therapy with AAV is not ideal for treating genetic diseases of the liver that manifest as newborns since the non-integrating genome is lost as developing liver cells proliferate. Because of this Wilson, co-first author Lili Wang, PhD, a research associate professor of Pathology and Laboratory Medicine, and collaborators, thought that the newborn liver might be an ideal organ for AAV-mediated gene correction using CRISPR-Cas9, an RNA-guided genome-editing technology that uses the bacteria protein Cas9. With CRISPR-Cas9 the corrected mutation will persist as the vector genome is lost. This hypothesis was tested in a mouse model of a rare metabolic urea-cycle disorder caused by a deficiency in an enzyme called ornithine transcarbamylase (OTC). The urea cycle is a series of six liver enzymes that help rid the body of ammonia, a breakdown product of protein metabolism. When one of these enzymes is missing or deficient, ammonia accumulates in the blood and travels to the brain, causing a multitude of problems, including brain damage and death. OTC deficiency is the most common of the urea-cycle disorders, occurring in one out of every 40,000 births. A mutated OTC gene can cause an enzyme that is shorter than normal, the wrong shape, or may not be produced at all. The genetic mutation responsible for OTC occurs on the X chromosome, so women are typically carriers, while their sons with the mutated gene suffer the disease. The team injected two AAVs (specifically an AAV8 serotype discovered in the Wilson lab that has an affinity for liver cells), one expressing Cas9 and the other expressing a guide RNA and a donor DNA, into newborn mice with OTC deficiency. One AAV ferried the Cas9 enzyme via a liver-specific promoter to ensure it only expresses in liver cells when injected into the blood. The other AAV in the dual system ferried a guide RNA - a 20-base string of genetic building blocks followed by another sequence to lead the Cas9 enzyme to the correct spot within the DNA in the nucleus of the liver cell. The second AAV also contained a donor DNA template to correct the mutation so that the normal OTC protein can be made by the cell. The addition of this donor DNA to actually correct a mutation distinguishes this study from other recent genome-editing research findings that circumvent a mutation by deleting a portion of the normal gene. This whole correction system is basically a "Cut-and-Paste" function, with the last part of the "Paste" phase relying on the cells' own DNA repair mechanism to properly join the OTC gene back together again. In the newborn mice, injection of the AAV system reverted the mutation in 10 percent of liver cells, on average, as measured by the presence of the OTC enzyme in liver cells. They also saw an increased survival in young mice challenged with a high-protein diet, which makes OTC-deficient symptoms worse in the mice. In contrast, more than 30 percent of the untreated OTC-deficient mice died after a week and their ammonia levels were significantly higher than the OTC mice whose genes were corrected. Deep sequencing of DNA isolated from liver cells in the treated mice also showed that correction to the mutation was consistent with the survival results. On the other hand, gene correction in adult, eight-to-ten-week-old OTC-deficient mice was lower using the same dual-AAV system. The adults also showed diminished protein tolerance and lethal hyperammonia on a normal chow diet. After three weeks, the adult mice on a low dose of the gene correction started to die, and counterintuitively, mice given a high dose started to die nine days after injection. "We were surprised by these results, but after some further investigation we deciphered the mechanism by which gene editing worsened the condition of the adult animals," Wang said. Looking at the DNA sequence in liver cells in adult mice, they found that the frequency of cells that had a corrected Paste function was only about one percent. "This was certainly not enough to help these adult mice," Wang noted. What was more problematic, and completely unexpected, is that many of the uncorrected genes contained large deletions that eliminated the residual activity of the mutant OTC gene. The first step in correcting the gene is the creation of a break in the DNA by Cas9 in proximity to the mutation (the Cut) which, in the presence of the donor DNA, sets the stage for correction of the mutation in what is termed homology directed repair (HDR or the Paste). "It appears that HDR is more efficient in newborn liver cells than in adult liver cells." Wilson said. In the absence of HDR the cell will repair the cut using another process called non-homologous end joining (NHEJ) that leaves in its wake small insertions or deletions. The team directed the cut to a part of the OTC gene that, if perturbed by a small insertion or deletion, would not interfere with the residual function of the mutant OTC gene. This was the case in newborn mice. The team learned, however, that NHEJ in adult liver cells resulted in much larger deletions, some of which eliminated any residual function of the OTC gene. The net result of low rates of the Paste with responses to the Cut that destroyed the remaining gene function in many cells resulted in lower tolerance to protein in adult mice. "The ontoward consequences of gene editing observed in adult OTC mice is limited to treating genetic diseases in which the mutation diminishes but does not eliminate function," Wilson explained. In an attempt to avoid this problem in certain adult patients with liver diseases, the team is exploring methods to create the Cut without inciting the large deletions while at the same time, driving higher frequencies of the Paste. Explore further: Researchers reverse a liver disorder in mice by correcting a mutated gene More information: A dual AAV system enables the Cas9-mediated correction of a metabolic liver disease in newborn mice, Nature Biotechnology, DOI: 10.1038/nbt.3469


Cromer W.,Gene Therapy Program | Jennings M.H.,Health science Center | Odaka Y.,Gene Therapy Program | Mathis J.M.,Gene Therapy Program | Alexander J.S.,Health science Center
Microcirculation | Year: 2010

Objective: To investigate the effects of the murine inhibitory vascular endothelial growth factor (VEGF, rVEGF164b), we generated an adenoviral vector encoding rVEGF164b, and examined its effects on endothelial barrier, growth, and structure. Method: Mouse vascular endothelial cells (MVEC) proliferation was determined by an MTT assay. Barrier of MVEC monolayers was measured by trans-endothelial electrical resistance (TEER). Reorganization of actin and zonula occludens-1 (ZO-1) were determined by fluorescent microscopy. Results: Mouse venous endothelial cells treated with murine VEGF-A (VEGF-A) (50 ng/mL) increased proliferation (60.7 ± 0.1%) within 24 hours (p < 0.05) and rVEGF164b inhibited VEGF-A-induced proliferation. TEER was significantly decreased by VEGF-A (81.7 ± 6.2% of control). Treatment with rVEGF164b at 50 ng/mL transiently reduced MVEC barrier (p < 0.05) at 30 minutes post-treatment (87.9 ± 1.7% of control TEER), and returned to control levels by 40 minutes post-treatment. Treatment with rVEGF164b prevented barrier changes by subsequent exposure to VEGF-A. Treatment of MVECS with VEGF-A reorganized F-actin and ZO-1, which was attenuated by rVEGF164b. Conclusions: VEGF-A may dysregulate endothelial barrier through junctional cytoskeleton processes, which can be attenuated by rVEGF164b. The VEGF-A stimulated MVEC proliferation, barrier dysregulation, and cytoskeletal rearrangement. However, rVEGF164b blocks these effects, therefore it may be useful for regulation studies of VEGFA/VEGF-R signaling in many different models. © 2010 John Wiley & Sons Ltd.

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