DOCSLIB.ORG

Precision Medicine As Treatment for Primary Immu- Nodeficiency and Immune Dysregulation

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Precision Medicine As Treatment for Primary Immu- Nodeficiency and Immune Dysregulation Archive of SID Immunology and Genetics Journal Received: 19 October 2019 Accepted: 24 November 2019 Review Article Published online: 22 December 2019 Doi: 10.22034/igj.2019.206436.1026 Precision Medicine as Treatment for Primary Immu- nodeficiency and Immune Dysregulation Rodrigo Hoyos-Bachiloglu1, Craig D. Platt2* 1 Department of Pediatric Infectious Diseases and Immunology,Pontificia Universidad Católica de Chile, Santiago, Chile 2 Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Abstract “Precision medicine” is the use of therapy that targets the molecular basis of a patient’s disease process. This approach is increasingly well-established in treatment of monogenic disorders of immunity, in- cluding primary immunodeficiencies and primary immune regulatory disorders. This is due to the exquisite detail with which many immune pathways have been defined, and the wide variety of immune modulatory medications that target these pathways. Here we review many of the most effective uses of this approach and suggest a framework for classifying these strategies. Keywords Precision medicine, Targeted therapy, Primary immunodeficiency disease, immune dys- regulation. * Corresponding author: Craig D. Platt E-mail: [email protected] 1. Department of Pediatric Infectious Diseases and Immunology,Pontificia Universidad Católica de Chile, Santiago, Chile2. Division of Immunology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA Introduction large and increasing repertoire of immune mod- Widespread availability of “next generation” se- ulatory medications, many designed for treating quencing techniques, including targeted sequenc- common autoimmune diseases, are available ing panels and whole exome sequencing has for use as targeted therapies. In this review, we ushered in an era where monogenic causes of im- present a framework for classifying “precision munodeficiency and immune dysregulation can medicine” strategies in hopes that this will aid be determined with speed and precision. When in understanding the use of these therapies and the mechanistic basis of the disease is known, a will assist the rational design of novel targeted therapies. The precision medicine strategies dis- www.SID.ir Hoyos-Bachiloglu, D. Platt Precision Medicine for PID Archive of SID cussed below fall into one of three categories: mune thrombocytopenic purpura and chronic in- 1) replacement of “missing molecules,” 2) inhi- flammatory demyelinating polyneuropathy, but bition of overactive intracellular signaling path- is used off-label for many more autoimmune and ways, and 3) cytokine blockade. inflammatory conditions (3). IVIG does not mod- ulate immune function through a single defined Replacement of “missing molecules” mechanism. Just a few of the proposed mecha- Monogenic defects frequently cause disease nisms include 1) blockade of Fc receptors on through disruption of the expression or function macrophages of the reticuloendothelial system, of a protein gene product. The simplest form of 2) blockade of adhesion molecules on leuko- precision medicine, infusion of the “missing mol- cytes, 3) saturation of FcRn receptors to enhance ecule” is not possible for the vast majority of dis- clearance of autoantibodies and 4) induction of orders, considering that the precise localization signaling through inhibitory FcγRIIB receptors of receptors, signaling molecules and other cel- on effector macrophages (4). lular components is typically necessary for their effective function. We discuss several notable Use of PEG-ADA in adenosine deami- exceptions below, where treatment involves sup- nase deficiency SCID plementation of defective pathways though infu- In 1972, Dr. Eloise Giblett and colleagues report- sion of WT proteins. (Note that gene therapy and ed two unrelated females with SCID who had no gene editing approaches are outside of the scope detectable adenosine-deaminase enzyme activity of this review, though in principle, these are the in their red blood-cells (5). A causal mechanism ultimate realization of this strategy). between ADA deficiency and defective lympho- Use of IVIG for antibody deficiency cyte function was defined, the first time that the Precision medicine was arguably part of the prac- molecular basis for immunodeficiency had been tice of clinical immunology since the earliest described. Later work elucidated that ADA de- days of the field. In the same report that Ogden ficiency is a disorder of purine metabolism that Bruton described agammaglobulinemia in an 8 leads to accumulation of toxic metabolites that year-old boy with recurrent pneumococcal sepsis, induces lymphocyte death and thymic dysfunc- otitis media, and pneumonia, he described effec- tion (6). tive treatment by replacing the patient’s missing In 1987, Hershfield et al. described intramuscu- IgG with subcutaneous immunoglobulin replace- lar infusion of bovine-derived ADA derived conju- ment (1). Modern immunoglobulin preparations, gated to polyethylene glycol (PEG-ADA) to treat purified and pooled from thousands of donors, a patient with ADA deficiency (7). This was the are routinely used for patients with antibody de- basis for an FDA-approved treatment for ADA- ficiency. Administered via intravenous or subcu- SCID through enzyme replacement. Weekly or taneous infusion, immunoglobulin replacement twice-weekly intramuscular injection of PEG-ADA provides levels of serum IgG comparable to those leads to sufficient plasma ADA levels to allow sur- from healthy subjects (2). This is remarkably ef- vival of lymphocyte progenitors and may also pro- fective at reducing rate of sinopulmonary infec- tect some ADA-deficient patients from hepatic and tions and preventing long-term complications neurologic dysfunction (8, 9). such as bronchiectasis (2). While not a form of Approximately 80% of patients have a signifi- precision medicine, it should be noted that IVIG cant response to enzyme replacement within 2-4 is also widely used for its immune modulatory months, including protection against opportunistic properties. It is FDA-approved for use in im- and life-threatening infections (9). Lymphocyte www.SID.ir www.igjournal.ir 9 Immunol Genet J (2019) 2(4):8-22 Precision Medicine for PID Hoyos-Bachiloglu, D. Platt Archive of SID number and function, however, rarely return to nor- mune dysregulation including lymphoproliferation, mal levels. Even among patients with an initially immune-mediated cytopenias, enteropathy, and en- robust response, a gradual decline in lymphocyte docrinopathies (16). As reduced CTLA-4 surface counts and function can be seen over time (9). This expression on T cells underlies the pathology in is in contrast to data from patients who have re- these disorders, infusion of CTLA-4 Ig (abatacept), ceived HSCT or gene therapy where available data a medication FDA approved for rheumatoid arthri- describes long-term stability of lymphocyte func- tis, has proven an incredibly powerful approach, as tion.10 While not a definitive treatment strategy, discussed further below. for patients without immediate access to such treat- When LRBA deficiency was discovered in 2012 ments, PEG-ADA enzyme replacement remains a through whole exome sequencing, the molecular potentially life-saving tool. mechanism of the disorder was not immediately PEG-ADA enzyme replacement therapy is unique clear (17, 18). However, in a seminal 2015 paper, among the precision therapies described in this re- Lo et al. described dramatic clinical improvement view as it is a true “orphan drug,” developed to treat in three LRBA-deficient patients treated with aba- the small population of patients with ADA defi- tacept (13). Patients demonstrated rapid improve- ciency and of no utility to patients with other forms ment in lung pathology as revealed by computed of SCID or immune dysregulation (8). Like other CT scan and pulmonary function testing, improve- orphan drugs, the cost is quite high, which limits ment or resolution of inflammatory and/or autoim- availability in resource-poor countries or in patients mune conditions, and normalization of biomarkers without access to high quality health insurance. of T cell dysregulation including soluble CD25 and With such medications, there is little likelihood of percentage of peripheral naïve T cells. This initially decreasing costs over time as there is no possibility unexpected response to abatacept led to the finding of scaling up production or competition from gener- that LRBA acts as a chaperone that directs intracel- ic or biosimilar products (11). lular trafficking of CTLA-4 to the cell surface, pre- venting lysosomal degradation (13). Abatacept to treat CLTA-4 Haploinsuf- A recent report has examined the long-term effica- ficiency and LRBA deficiency cy of abatacept in 18 patients with LRBA deficien- Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a cy (19). In 16 of these patients there was substantial critical T cell inhibitory molecule present on ac- long-term improvement. There was near complete tivated T cells and regulatory T cells (Tregs) that control of lymphoproliferation and chronic diar- restrains immune responses by interfering with rhea, as well as significant improvement in autoim- T cell costimulation by antigen presenting cells. mune cytopenias. Two biomarkers of disease ac- The inhibitory properties of this molecule are due tivity, soluble CD25 and percentage of peripheral to its ability to block interaction of CD28 on T regulatory T cells, correlated well with response
Load more

Recommended publications
  • HUMAN GENE MAPPING WORKSHOPS C.1973–C.1991
    HUMAN GENE MAPPING WORKSHOPS c.1973–c.1991 The transcript of a Witness Seminar held by the History of Modern Biomedicine Research Group, Queen Mary University of London, on 25 March 2014 Edited by E M Jones and E M Tansey Volume 54 2015 ©The Trustee of the Wellcome Trust, London, 2015 First published by Queen Mary University of London, 2015 The History of Modern Biomedicine Research Group is funded by the Wellcome Trust, which is a registered charity, no. 210183. ISBN 978 1 91019 5031 All volumes are freely available online at www.histmodbiomed.org Please cite as: Jones E M, Tansey E M. (eds) (2015) Human Gene Mapping Workshops c.1973–c.1991. Wellcome Witnesses to Contemporary Medicine, vol. 54. London: Queen Mary University of London. CONTENTS What is a Witness Seminar? v Acknowledgements E M Tansey and E M Jones vii Illustrations and credits ix Abbreviations and ancillary guides xi Introduction Professor Peter Goodfellow xiii Transcript Edited by E M Jones and E M Tansey 1 Appendix 1 Photographs of participants at HGM1, Yale; ‘New Haven Conference 1973: First International Workshop on Human Gene Mapping’ 90 Appendix 2 Photograph of (EMBO) workshop on ‘Cell Hybridization and Somatic Cell Genetics’, 1973 96 Biographical notes 99 References 109 Index 129 Witness Seminars: Meetings and publications 141 WHAT IS A WITNESS SEMINAR? The Witness Seminar is a specialized form of oral history, where several individuals associated with a particular set of circumstances or events are invited to meet together to discuss, debate, and agree or disagree about their memories. The meeting is recorded, transcribed, and edited for publication.
    [Show full text]
  • Rare Immunodeficiency Unanticipated
    Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency This information is current as Michael R. Blackburn and Linda F. Thompson of October 4, 2021. J Immunol 2012; 188:933-935; ; doi: 10.4049/jimmunol.1103519 http://www.jimmunol.org/content/188/3/933 Downloaded from References This article cites 24 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/188/3/933.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on October 4, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency Michael R. Blackburn* and Linda F. Thompson† he serendipitous discovery of adenosine deaminase ciated gouty arthritis (2), but this pathway was not thought (ADA) deficiency in two patients with cellular im- to be important for the immune system.
    [Show full text]
  • Eloise Giblett, Or Elo As She Preferred to Be Called, Was Born in Tacoma, Washington in 1921
    Eloise R. Giblett 1921–2009 A Biographical Memoir by Arno G. Motulsky and Stanley M. Gartler ©2017 National Academy of Sciences. Any opinions expressed in this memoir are those of the authors and do not necessarily reflect the views of the National Academy of Sciences. ELOISE R. GIBLETT January 17, 1921–September 16, 2009 Elected to the NAS, 1980 Eloise Giblett, or Elo as she preferred to be called, was born in Tacoma, Washington in 1921. Her mother had been reading “Eloise and Abelard” during her pregnancy and was so taken with the famous love story that she chose the name Eloise for her daughter. Her mother also gave Eloise a love of music, dance, and song—for a short period as a child, Eloise was thought to have the potential to become a second Shirley Temple. At the time of Elo’s birth, her father was a machinist working on the ship- building docks around Tacoma. When Eloise and her older brother started school, their father became an insurance salesman for the Metropolitan Life Insurance Company. Successful at his new job, he was promoted to manager of By Arno G. Motulsky the Spokane office, and the family moved there and lived and Stanley M. Gartler a comfortable life through the Great Depression. Elo did well in school and excelled at the violin but was not particularly interested in science in her early years. That changed when her brother told her about a high school chemistry course he was taking and she became fascinated with atoms and molecules. Thereafter, she started taking science courses while still maintaining her interest in music.
    [Show full text]
  • Role of Purines in Lymphocyte Function *
    Role of Purines in Lymphocyte Function * H. Kyle Webster, Ph.D. A II cells require a balanced supply disease (SCID) whose RBC and neous hypersensitivity and reduced of purines for growth, proliferation other tissues lacked the enzyme responsiveness of lymphocytes to and sllrvival. The major roles of adenosine deaminase (ADA). The mitogens, allogeneic cells, and other purines in cellular metabolism and nex t year ten more cases of SCID antigens. 1 There is severe h ypo­ function are given in Table I. In associated ADA deficiency were re­ gammagloblulinaemia 0 r agamma­ Figure I, a simplified outline is ported. The parents of affected globulinaemia with no evidence of shown of the basic pathways by children were found to have re­ specific antibody synthesis. Such which purines are metabolised. The duced RBC ADA activity indicating individuals are prone to increasingly purpose of this article is to review an autosomal recessive form of the severe infections with eventual fatal those aspects of purines that appear disease. Thus it appeared that at outcome in the absence of success­ unique to lymphocytes and thus least some forms of immunodefi­ ful therapy. Successful immuno­ their functions in immune pro­ ciency disease were "inborn errors logical reconstitution has been cesses. Basically, the rationale for of metabolism." achieved in ADA deficient SCID this focus comes from the involve­ Adenosine deaminase (adenine patients with histocompatible bone ment of purines in immunodefi­ aminohydrolase) (E.C. 3.5.4.4) marrow transplantation.6 Another ciency diseases a nd the use 0 f catalyses the irreversible deamina­ therapy effective in some indivi- purine analogues as immunosup­ tion of adenosine to inosine or de­ pressive agents.
    [Show full text]
  • 1 April 10, 2020 DONALD BARRY KOHN, M.D. Curriculum Vitae A
    DONALD BARRY KOHN, M.D. Curriculum Vitae A. PERSONAL INFORMATION Business Address Departments of Microbiology, Immunology & Molecular Genetics (M.I.M.G.); Pediatrics (Division of Hematology/Oncology); and Molecular & Medical Pharmacology University of California, Los Angeles David Geffen School of Medicine 3163 TLSB, 610 Charles E. Young Drive East Los Angeles, CA 90095 Business Phone (310) 794-1964 Fax (310) 206-0356 E-mail [email protected] Citizenship United States B. EDUCATION High School New Trier West-Northfield, IL 1972 B.S. Biology University of Illinois-Urbana 1976 M.S. Microbiology University of Illinois-Urbana 1978 “Tumor protease-activated pro-drugs” M.D. Medicine University of Wisconsin-Madison 1982 Board Certification: American Board of Pediatric 1988 Medical Licensure: Wisconsin 1982- present California 1987- present 1 April 10, 2020 C. PROFESSIONAL EXPERIENCE Present Position: Professor, Departments of Microbiology, Immunology & Molecular Genetics (MIMG); Pediatrics, (Division of Hematology/Oncology); and Molecular and Medical Pharmacology; UCLA David Geffen School of Medicine, University of California, Los Angeles (UCLA). 2009–present. Director, UCLA Human Gene and Cell Therapy Program, 2009–present. Previous Positions held: Teaching Assistant, Department of Microbiology, University of Illinois-Urbana, 1976-77. Research Assistant, Dept. of Microbiology, University of Illinois-Urbana, 1977-78. Internship, Department of Pediatrics, University of Wisconsin-Madison, 1982-83. Residency, Department of Pediatrics, University of Wisconsin-Madison, l983-85. Fellowship, Immunology - Dr. R. Michael Blaese, Metabolism Branch, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD, l985-87. Attending Physician, Bone Marrow Transplantation, Childrens Hospital Los Angeles 1987 – 2008. Instructor, Department of Pediatrics, University of Southern California School of Medicine at Division of Research Immunology and Bone Marrow Transplantation, Childrens Hospital Los Angeles, 1987-89.
    [Show full text]
  • Journal of Blood Group Serology and Education
    Immunohematology Journal of Blood Group Serology and Education Celebrating 2Yea5rs Volume 26, Number 1, 2010 Immunohematology Journal of Blood Group Serology and Education Volume 26, Number 1, 2010 Contents Letter to the Readers 1 G.M. Meny Review The Knops blood group system: a review 2 J.M. Moulds Case Report Role for serial prenatal anti-Vel quantitative serologic monitoring 8 with 2-ME serum treatment W.J. Linz, J.T. Fueger, S. Allen, and S.T. Johnson Review Granulocyte serology: current concepts and clinical significance 11 M.E. Clay, R.M. Schuller, and G.J. Bachowski Review A review of the Colton blood group system 22 G.R. Halverson and T. Peyrard Case Report 27 Alloimmunization to the D antigen by a patient with weak D type 21 H. McGann and R.E. Wenk Review A review of the Chido/Rodgers blood group 30 R. Mougey In Memoriam 39 Marie Cutbush Crookston (1920–2009) D. Mallory 40 In Memoriam Eloise Giblett (1921–2009) D. Mallory 41 Announcements 42 Advertisements 46 Instructions for Authors Editors-in-Chief Managing Editor Sandra Nance, MS, MT(ASCP)SBB Cynthia Flickinger, MT(ASCP)SBB Philadelphia, Pennsylvania Philadelphia, Pennsylvania Connie M. Westhoff, PhD, MT(ASCP)SBB Technical Editors Philadelphia, Pennsylvania Christine Lomas-Francis, MSc New York City, New York Senior Medical Editor Geralyn M. Meny, MD Dawn M. Rumsey, ART (CSMLT) Philadelphia, Pennsylvania Glen Allen, Virginia Associate Medical Editors David Moolten, MD Ralph R. Vassallo, MD Philadelphia, Pennsylvania Philadelphia, Pennsylvania Editorial Board Patricia Arndt, MT(ASCP)SBB Brenda J. Grossman, MD Mark Popovsky, MD Pomona, California St.
    [Show full text]
  • Development of Transition State Analogues of Purine Nucleoside Phosphorylase As Anti-T-Cell Agents
    Biochimica et Biophysica Acta 1587 (2002) 107–117 www.bba-direct.com Review Development of transition state analogues of purine nucleoside phosphorylase as anti-T-cell agents Vern L. Schramm* Department of Biochemistry, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forch. 308, Bronx, NY 10461, USA Received 24 January 2002; accepted 24 January 2002 Abstract Newborns with a genetic deficiency of purine nucleoside phosphorylase (PNP) are normal, but exhibit a specific T-cell immunodeficiency during the first years of development. All other cell and organ systems remain functional. The biological significance of human PNP is degradation of deoxyguanosine, and apoptosis of T-cells occurs as a consequence of the accumulation of deoxyguanosine in the circulation, and dGTP in the cells. Control of T-cell proliferation is desirable in T-cell cancers, autoimmune diseases, and tissue transplant rejection. The search for powerful inhibitors of PNP as anti-T-cell agents has culminated in the immucillins. These inhibitors have been developed from knowledge of the transition state structure for the reactions catalyzed by PNP, and inhibit with picomolar dissociation constants. Immucillin- H (Imm-H) causes deoxyguanosine-dependent apoptosis of rapidly dividing human T-cells, but not other cell types. Human T-cell leukemia cells, and stimulated normal T-cells are both highly sensitive to the combination of Imm-H to block PNP and deoxyguanosine. Deoxyguanosine is the cytotoxin, and Imm-H alone has low toxicity. Single doses of Imm-H to mice cause accumulation of deoxyguanosine in the blood, and its administration prolongs the life of immunodeficient mice in a human T-cell tissue xenograft model.
    [Show full text]
  • Immunohematology
    Immunohematology Journal of Blood Group Serology and Education Celebrating 2 Yea5rs Volume 25, Number 2, 2009 Immunohematology Journal of Blood Group Serology and Education Volume 25, Number 2, 2009 Contents Invited Review: Milestones Series 39 Milestones in laboratory procedures and techniques M.E. Reid Case Report 44 Anti-Kpa–induced severe delayed hemolytic transfusion reaction R. Koshy, B. Patel, and J.S. Harrison Review 48 The ABO blood group system revisited: a review and update J.R. Storry and M.L. Olsson Case Report 60 Clinical evaluation for lymphoproliferative disease prompted by finding of IgM warm autoanti-IT in two cases R.M. Leger, F. Lowder, M.C. Dungo, W. Chen, H.M. Mason, and G. Garratty Original Report 63 Southeast Asian ovalocytosis is associated with increased expression of Duffy antigen receptor for chemokines (DARC) I.J. Woolley, P. Hutchinson, J.C. Reeder, J.W. Kazura, and A. Cortés Review 67 Sickle cell disease: a review S.D. Roseff Report 75 Consortium for Blood Group Genes (CBGG): 2008 report G.A. Denomme, C.M. Westhoff, L. Castilho, and M.E. Reid for the CBGG Special Dedication 81 W. John Judd, FIBMS, MIBiol D. Mallory 82 Letter from the Editors 83 Announcements 84 Advertisements 88 Instructions for Authors Editors-in-Chief Managing Editor Sandra Nance, MS, MT(ASCP)SBB Cynthia Flickinger, MT(ASCP)SBB Philadelphia, Pennsylvania Philadelphia, Pennsylvania Connie M. Westhoff, PhD, MT(ASCP)SBB Technical Editor Philadelphia, Pennsylvania Christine Lomas-Francis, MSc New York City, New York Senior Medical Editor Geralyn M. Meny, MD Philadelphia, Pennsylvania Associate Medical Editors David Moolten, MD Ralph R.
    [Show full text]
  • Rare Immunodeficiency Unanticipated
    Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency This information is current as Michael R. Blackburn and Linda F. Thompson of September 27, 2021. J Immunol 2012; 188:933-935; ; doi: 10.4049/jimmunol.1103519 http://www.jimmunol.org/content/188/3/933 Downloaded from References This article cites 24 articles, 9 of which you can access for free at: http://www.jimmunol.org/content/188/3/933.full#ref-list-1 Why The JI? Submit online. http://www.jimmunol.org/ • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average by guest on September 27, 2021 Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2012 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Adenosine Deaminase Deficiency: Unanticipated Benefits from the Study of a Rare Immunodeficiency Michael R. Blackburn* and Linda F. Thompson† he serendipitous discovery of adenosine deaminase ciated gouty arthritis (2), but this pathway was not thought (ADA) deficiency in two patients with cellular im- to be important for the immune system.
    [Show full text]
  • Facilitating End-To-End Development of Individualized Therapeutics Public Workshop U.S
    Facilitating End-to-End Development of Individualized Therapeutics Public Workshop U.S. Food and Drug Administration Center for Biologics Evaluation and Research (CBER) FDA White Oak Campus 10903 New Hampshire Ave. Bldg. 31 Conference Center Great Room Silver Spring, MD 20993 March 3, 2020 This transcript appears as received from the commercial transcribing service after inclusion of minor corrections to typographical and factual errors recommended by the DFO 2 ATTENDEES Albert B. Seymour, PhD Homology Medicines, Inc. Alison Bateman-House, PhD, MPH, MA NYU Grossman School of Medicine Donald B. Kohn, MD UCLA Guangping Gao, PhD University of Massachusetts Jason J. Gill, PhD Texas A&M University Jill A. Wood Phoenix Nest J. Keith Joung, MD, PhD Massachusetts General Hospital Malachi Griffith, PhD Washington University School of Medicine Philip John (PJ) Brooks, PhD National Institutes of Health Robert T. (Chip) Schooley, MD University of California San Diego Center for Biologics Evaluation and Research Gopa Raychaudhuri, PhD (CBER) Center for Biologics Evaluation and Research Peter Marks, MD, PhD (CBER) Center for Biologics Evaluation and Research Zenobia Taraporewala, PhD (CBER) Center for Biologics Evaluation and Research Roger Plaut, PhD (CBER) Center for Biologics Evaluation and Research Anita Richardson, MAS (CBER) Center for Biologics Evaluation and Research Sandhya Sanduja, PhD (CBER) Center for Biologics Evaluation and Research Zuben Sauna, PhD (CBER) Center for Biologics Evaluation and Research Rebecca Reindel, MD (CBER) Center for Biologics Evaluation and Research Larissa Lapteva, MD (CBER) Center for Biologics Evaluation and Research Zhenzhen Xu, PhD (CBER) www.transcriptionetc.com 3 Center for Biologics Evaluation and Research Celia Witten, PhD, MD (CBER) Center for Biologics Evaluation and Research Capt.
    [Show full text]
  • The Americansociety for Clinical Investigation
    PROCEEDINGS OF THE FORTY-EIGHTH ANNUAL MEETING OF THE AMERICAN SOCIETY FOR CLINICAL INVESTIGATION HELD IN ATLANTIC CITY, N. J., APRIL 30, 1956 PRESIDENTIAL ADDRESS THE INDIVIDUAL IN MEDICAL RESEARCH AND THE ROLE OF THE UNIVERSITY CENTER IN HIS TRAINING By A. MCGEHEE HARVEY It is the custom that there be a Presidential address. versity Center is the medical storage battery for the My thesis is not new. It concerns the importance of the training of investigators. individual in research and of the University Medical The University is represented by a single active cell. Center in his training. Within the University are schools indicated by mito- This Society was established as a meeting ground for chondria, one of which is the University Medical Center. those interested in clinical investigation in its broad- (Fig. 1, A and B.) When the intact mitochondrium is est aspects. If it has a fundamental objective, it is the working in the presence of molecular oxygen, oxidation creation and preservation of a "Heritage of Excellence" of food stuffs is completed, phosphorylation occurs, and in research. The term "heritage of excellence" was ATP is formed. To carry out its objectives completely, coined by Alan Gregg as a penetrating expression of the the Medical Center must have molecular oxygen in the abiding influence of Dr. Welch and his associates on the form of strong academic and financial support. The spirit of creative scholarship at the Johns Hopkins Medi- mitachondrial membrane is selectively permeable; only cal Institutions. those factors essential to operation of the cycle gain en- It is important for University clinics to provide and to trance.
    [Show full text]
  • Human Purine Metabolism: Some Recent Advances and Relationships with Immunodeficiency
    Ann Rheum Dis: first published as 10.1136/ard.42.Suppl_1.8 on 1 January 1983. Downloaded from Ann Rheum Dis (1983), 42, Supplement p 8 Human purine metabolism: some recent advances and relationships with immunodeficiency GEORGE NUKI From the Rheumatic Diseases Unit, Department ofMedicine (WGH), University ofEdinburgh Studies of human purine metabolism 0-6 g (3-6 mmol) while on a 10-9 MJ balanced interaction of several began some 200 years ago with (2600 kilocalorie), 70 g protein, biochemical pathways (Fig. 1). Purine Scheele's identification of uric acid as a purine-free diet is generally taken to biosynthesis de novo consists of a constituent of a renal calculus' and be abnormal,5 but recent data on series of 10 enzymatic steps in which Wollaston's demonstration of urate in healthy Australians on low purine glutamine, glycine, carbon dioxide, a tophus from his own ear.2 Just as diets showed mean urinary urates of aspartate, and 1-carbon-formyl these were among the earliest 3-9 mmol (0 65 g)/24 hrs for men and derivatives of folate are added to the experiments in the new science of 2-9 mmol (0.5 g)/24 hrs for women.6 ribose moiety of phosphoribosyl biochemistry, so Garrod's (1854)3 A variety of mutations of three pyrophosphate (PRPP) to form thread test must rank as the first assay enzymes are associated with excessive inosinic acid (IMP). Adenosine in what we now call the discipline of purine synthesis in patients with gout, monophosphate (AMP) and clinical chemistry. Seegmiller's but these account for only a small guanosine monophosphate (GMP) are discovery, 15 years ago, that the severe proportion of those identified as each formed from IMP by two purine overproduction and gout primary overproducers of urate.
    [Show full text]