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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.


CINCINNATI--Researchers at the University of Cincinnati (UC) have found that a cancer stem cell vaccine, engineered to express a pro-inflammatory protein called interleukin-15 (IL-15) and its receptor (IL-15Ralpha), caused T cell production in animal models and enhanced immune responses against tumors. This T cell production showed a cellular immune response that could lead to new immunotherapy treatments for cancer with improved side effects. These findings are being presented via poster abstract at the American Society of Gene and Cell Therapy's annual meeting in Washington, D.C., May 10-13. "IL-15 is a powerful stimulator of the maturation and activation of T cells and natural killer cells that recognize and attack tumor cells. Human IL-15 was first used in Phase I clinical trials to test its efficacy for treatment of a number of cancers, including melanoma and kidney cancer, but caused a number of side effects that made high doses difficult for patients to tolerate," says John Morris, MD, co-author of this study, clinical co-leader of the Molecular Therapeutics and Diagnosis Program for the Cincinnati Cancer Consortium, co-leader of the UC Cancer Institute's Comprehensive Lung Cancer Program, professor in the Division of Hematology Oncology at the UC College of Medicine and UC Health medical oncologist. "In this work, we showed that transferring the genes for both IL-15 with its receptor into cancer cells increased the cell-surface presentation of IL-15 to T cells, and in turn, stopped the tumor cells from reproducing with little evidence of side effects in animal models. "In an effort to enhance antitumor activity and reduce side effects, we studied a vaccine targeting cancer stem cells, the cells in a tumor thought to be resistant that give rise to recurrent tumors after treatment, by genetically altering them to express IL-15 and IL-15Ralpha to see if lung cancers implanted in animal models shrunk." Using animal models and their lung cancer cell lines, researchers introduced the IL-15/IL-15Ralpha-modified lung cancer stem cells as a vaccine and saw dramatically reduced tumor growth. "Animal lung cancer stem cells expressing IL-15 and IL-15Ralpha stimulated proliferation of T cells suggesting the ability to enhance immune responses," he says. "These findings further support evidence of IL-15's ability as a cancer treatment. We are continuing vaccination studies in animal models with hopes of moving this research to a Phase I trial in humans to see if side effects are reduced." Donatien Toukam, PhD, post-doctoral fellow in the Division of Hematology Oncology, is the lead author of this study funded in part by the Lcs Foundation. He cites no conflicts of interest.


Wang L.,Molecular Therapeutics
Current Opinion in Pharmacology | Year: 2011

FK506 binding protein 51 (FKBP51, also called FKBP5) belongs to a family of immunophilins, FK506 binding proteins (FKBPs). FKBP family members are targets for drugs such as rapamycin. Although FKBP51 shares characteristics with other FKBPs, it also has unique features, especially the role in its regulation of important signaling pathways such as the AKT kinase/protein kinase B pathway. In this review, we will focus on the function of FKBP51 as a scaffolding protein in the regulation of AKT activation and, in turn, its role in tumorigenesis and response to chemotherapy. © 2011 Elsevier Ltd. All rights reserved.


Recent progress in enzyme engineering has led to versions of human butyrylcholinesterase (BChE) that hydrolyze cocaine efficiently in plasma, reduce concentrations reaching reward neurocircuity in the brain, and weaken behavioral responses to this drug. Along with enzyme advances, increasingly avid anti-cocaine antibodies and potent anti-cocaine vaccines have also been developed. Here we review these developments and consider the potential advantages along with the risks of delivering drug-intercepting proteins via gene transfer approaches to treat cocaine addiction. © 2011 Bentham Science Publishers.


Merriam-Webster's online dictionary defines purgatory as "an intermediate state after death for expiatory purification" or more specifically as "a place or state of punishment wherein according to Roman Catholic doctrine the souls of those who die in God's grace may make satisfaction for past sins and so become fit for heaven." Alternatively, it is defined as "a place or state of temporary suffering or misery." Either way, purgatory is a place where you are stuck, and you don't want to be stuck there. It is in this context that the term genetic purgatory is introduced. Genetic purgatory is a place where the genetic test-ordering physician and patients and their families are stuck when a variant of uncertain/unknown significance (VUS) has been elucidated. It is in this dark place where suffering and misery are occurring because of unenlightened handling of a VUS, which includes using the VUS for predictive genetic testing and making radical treatment recommendations based on the presence or absence of a so-called maybe mutation. Before one can escape from this miserable place, one must first recognize that one is stuck there. Hence, the purpose of this review article is to fully expose the VUS issue as it relates to the cardiac channelopathies and make the cardiologists/geneticists/genetic counselors who order such genetic tests believers in genetic purgatory. Only then can one meaningfully attempt to get out of that place and seek to promote a VUS to disease-causative mutation status or demote it to an utterly innocuous and irrelevant variant. © 2015 Heart Rhythm Society.


Hall I.P.,Molecular Therapeutics
European Respiratory Review | Year: 2013

It is well recognised that genetic factors play a major role in the development of respiratory diseases such as asthma and chronic obstructive pulmonary disease. However, whilst extensive data exist on diseases caused primarily by single gene defects, such as α1-antitrypsin deficiency, the genetic factors responsible for the development of complex disease are only now being defined. Once the gene(s) responsible for the heritable element of disease risk are known, the next step is to identify the mechanisms underlying the pathophysiological effects of the causal mutations in these genes. This process can be time consuming, but allows a full understanding of the mechanisms underlying disease development to be obtained. This knowledge can then potentially be used to stratify patient groups within (or even across) disease boundaries and then to target therapy more effectively. © ERS 2013.


Jones C.,Molecular Therapeutics | Baker S.J.,St Jude Childrens Research Hospital
Nature Reviews Cancer | Year: 2014

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation, as well as developmental signalling pathways. These new genetic findings give insights into disease pathogenesis and the challenges and opportunities for improving patient survival in these mostly incurable childhood brain tumours. © 2014 Macmillan Publishers Limited. All rights reserved.


Kenakin T.P.,Glaxosmithkline | Miller L.J.,Molecular Therapeutics
Pharmacological Reviews | Year: 2010

It is useful to consider seven transmembrane receptors (7TMRs) as disordered proteins able to allosterically respond to a number of binding partners. Considering 7TMRs as allosteric systems, affinity and efficacy can be thought of in terms of energy flow between a modulator, conduit (the receptor protein), and a number of guests. These guests can be other molecules, receptors, membrane-bound proteins, or signaling proteins in the cytosol. These vectorial flows of energy can yield standard canonical guest allostery (allosteric modification of drug effect), effects along the plane of the cell membrane (receptor oligomerization), or effects directed into the cytosol (differential signaling as functional selectivity). This review discusses these apparently diverse pharmacological effects in terms of molecular dynamics and protein ensemble theory, which tends to unify 7TMR behavior toward cells. Special consideration will be given to functional selectivity (biased agonism and biased antagonism) in terms of mechanism of action and potential therapeutic application. The explosion of technology that has enabled observation of diverse 7TMR behavior has also shown how drugs can have multiple (pluridimensional) efficacies and how this can cause paradoxical drug classification and nomenclatures. Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics.


Kenny P.J.,Molecular Therapeutics | Kenny P.J.,Scripps Research Institute
Nature Reviews Neuroscience | Year: 2011

The hedonic properties of food can stimulate feeding behaviour even when energy requirements have been met, contributing to weight gain and obesity. Similarly, the hedonic effects of drugs of abuse can motivate their excessive intake, culminating in addiction. Common brain substrates regulate the hedonic properties of palatable food and addictive drugs, and recent reports suggest that excessive consumption of food or drugs of abuse induces similar neuroadaptive responses in brain reward circuitries. Here, we review evidence suggesting that obesity and drug addiction may share common molecular, cellular and systems-level mechanisms. © 2011 Macmillan Publishers Limited. All rights reserved.

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