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Down Syndrome Quarterly Volume 9 Issue 2, 2007

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Down Syndrome Quarterly Volume 9 Issue 2, 2007 Official Publication of Down Syndrome International DSQ Down Syndrome Quarterly Volume 9 Issue 2, 2007 Published by the Together.Down Hand in Hand. Syndrome Research Foundation Down Syndrome Quarterly EXECUTIVE EDITORS HEALTH/INTERVENTION MEDICAL/GENETICS PERCEPTION/COGNITION SOCIAL DEVELOPMENT EDUCATION Elizabeth Kay-Raining Bird Cheryl Wellington Matthew Heath Deborah Fidler Monica Cuskelly Ph.D. Ph.D. Ph.D. Ph.D. Ph.D. Dalhousie University University of British Columbia University of Western Ontario Colorado State University University of Queensland EDITORIAL BOARD Roy Brown, Ph.D. Down Syndrome Research Foundation William Cohen, M.D. INTERNATIONAL University of Minnesota BOOK REVIEW CORRESPONDENTS COORDINATOR Jesus Florez, Ph.D. Patrick Clark University of Cantabria Robert Melrose, M.L.I.S. Ireland Librarian, DSRF Robert Haslam, M.D. Vanessa Dos Santos Emeritus, University of Toronto South Africa Eiichi Momotani Ira Lott, M.D. Japan Irvine University Penny Robertson Anne Jobling, Ph.D. Indonesia University of Queensland Balbir Singh Sigfried Pueschel, M.D. Singapore Harvard University ABSTRACTS COORDINATOR Bridget Snedden Sam Thios, Ph.D. New Zealand Denison University David S Smith, M.D. Paul Zanon Naznin Virji-Babul, Ph.D. Medical College United Kingdom Down Syndrome Research Foundation of Wisconsin Daniel Weeks, Ph.D. Simon Fraser University Jennifer Wishart, Ph.D. Edinburgh University ASSOCIATE EDITORS Len Leshin, M.D. Brian Maraj, Ph.D. Joanne Nye, Ph.D. Paediatrician & Parent, Corpus Christi, Texas University of Alberta University of Bristol Dominic Simon, Ph.D. Sarah Wood, Ph.D. New Mexico State University Queen Margaret University College. Edinburgh MANAGING EDITOR Josephine Mills, M.S.M. 2 DOWN SYNDROME QUARTERLY • VOLUME 9 • ISSUE 2 • MAY 2007 Down Syndrome Quarterly The aim of the Down Syndrome Quarterly (DSQ) is to provide easy access to research papers and evaluated results for clinicians, professionals, and families. The journal will have a broad focus and cover a wide range of topics relating to contents Down syndrome. It will include relevant research abstracts, commentaries relating the research to practice, peer reviewed VOLUME 9 • ISSUE 2 • MAY 2007 research papers, literature reviews, and regional reports. It will include reports and international work, especially encouraging submissions from developing countries. There will be the opportunity to exchange ideas, and discussion papers on key research issues will be included. The Applications and Potential of RNA Interference for Down Syndrome Research and Therapy The small editorial board will ensure that the journal achieves its PAGES 4–7 mandate and goals. An international and widely knowledgable review board will act as reviewers and commentators. Contact commentary will be developed with regional representatives to encourage Social Ethics and Values Leadership participation from all areas. and their Effect on the Life Prospects of People with Disabilities subscription information PAGES 8–12 In Print: Individual ...........................................$45** per year publications DSI / IASSID Members ......................$30** per year DSQ 2007 Selected Citations Organization / Library* .......................$85** per year PAGES 13–17 ** Plus Postage: Canada ..................................................$5 per year Global Books in Print & Book Reviews USA .......................................................$8 per year PAGE 18–20 International .........................................$16 per year international Online: Individual .............................................$30 per year World Down Syndrome Day — March 21 DSI / IASSID Members ........................$20 per year PAGE 21–23 * Includes In Print and Online subscriptions. Signing of the UN Convention on the All prices listed are in CDN$. Rights of Persons with Disabilities Prices do not include national or international postal delivery. PAGE 24 Orders should be sent to: down syndrome international Down Syndrome Quarterly 1409 Sperling Avenue DSI Strategic Plan — 2007 to 2009 PAGE 25–26 Burnaby, B.C Canada V5B 4J8 ISSN 1087-1756 DOWN SYNDROME QUARTERLY • VOLUME 9 • ISSUE 2 • MAY 2007 3 The Applications and Potential of RNA Interference for Down Syndrome Research and Therapy An Initial Review: Part I By Thomas J. Torda Corresponding Information Independent Contract Engineer Thomas J. Torda, Ph.D. Fairfax, VA, USA 12197 Wild Horse Drive, Fairfax VA, USA 22033 © 2007 by Thomas J. Torda email: [email protected] Abstract The present study, aimed at the educated layman (while keeping the specialist in mind) and intended as an update to a previous DSQ paper (Torda, 1998), attempts an initial review of the applications and potential of RNA interference (RNAi) for Down syndrome (DS) research and therapy, based on PubMed studies and a few online sources. The goal of this review which, to the author’s knowledge, has not previously been attempted, is to contribute some thought-provoking ideas on RNAi-based applications and potential therapies for DS, as well as to provide a review of recent (2000-2006) milestones in DS molecular genetics research that provide a foundation for applications of RNAi. Such milestones as the publication of the human chromosome 21 sequence, the first DS-patient stem cell research, and recent (June 2006) breakthroughs in DS signaling pathway research focusing on just two critical genes (DSCR1 and DYRK1A) — as well as a major breakthrough in targeted delivery of RNAi-mediated therapeutics into primates and significant progress in large-scale screening techniques — suggest that tools are in place for RNAi-based therapy for DS in the foreseeable future.Two tables. research Keywords: Down syndrome; RNA interference (RNAi); Applications; Potential; Therapies Introduction 1. Brief History and Fundamentals of RNAi In late 2006, the Nobel Committee announced that the Nobel Over two decades ago, two groups (Mizuno et al., 1984; Izant Prize in Physiology or Medicine 2006 had been awarded to and Weintraub, 1984) studying expression of the E. coli ompF Profs. Andrew Z. Fire of Stanford University and Craig C. Mel- gene and of the herpes simplex virus thymidine kinase gene, lo of the University of Massachusetts Medical School. Dr. Ber- respectively, found that “anti-sense RNA” can bind to a comple- til Daneholt, a Swedish professor of molecular genetics and mentary sequence in messenger RNA (mRNA), and thus inhibit Chairman of the Nobel Assembly, stated that this award was translation. (Translation is the process wherein the gene-tran- for “...their discovery [Fire et al., 1998] that double-stranded scribed mRNA is expressed with the aid of transfer RNA into a RNA triggers suppression of gene activity in a homology-de- protein; the anti-sense RNA nucleotides that are complemen- pendent manner, a process named RNA interference (RNAi). tary to the mRNA nucleotides A, C, G and U are U, G, C, and Their discovery revealed a new mechanism for gene regula- A, respectively) Six years later, two other groups (Napoli et al., tion, and the biochemical machinery involved plays a key role 1990; van der Krol et al., 1990) reported “homology-dependent in many essential cellular processes. Today, double-stranded gene silencing” in petunias—the phenomenon whereby incor- RNA is used as a powerful tool to experimentally elucidate poration of a cloned gene into a genome not only can stimulate the function of essentially any gene in a cell. The discovery of gene activity, but also can inhibit expression of homologous RNAi has already had an immense impact on biomedical re- sequences; this type of gene silencing occurred at the post- search and will most likely lead to novel medical applications transcription level, and thus was called “post-transcriptional in the future” (Daneholt, 2006). gene silencing” (PTGS). Other groups extended PTGS to the animal kingdom, specifically to the nematode Caenorhab- This enormously influential technique – as evidenced by a Janu- ditis elegans (Wightman et al., 1993); discovered that both ary 2007 PubMed search on “RNA interference” which returned “sense RNA” (i.e. RNA with the same base-pair sequence as 8500 articles, 5000 of which were published since January 2005 mRNA) and anti-sense RNA could generate PTGS in C. el- – has revolutionized biotechnology in laboratories worldwide. egans (Guo and Kemphues, 1995); and compared the PTGS effects of sense and anti-sense RNA (Jorgensen et al., 1996). The text is organized into an introduction and five sections: (1) a brief history and basic principles of RNAi; (2) a brief With this foundation, Profs. Fire and Mello and colleagues (Fire summary of the significance of RNAi; (3) recent (2000-2006) et al., 1998) resolved the puzzle of sense vs. anti-sense RNA milestones and major developments in DS molecular biology by first predicting the phenotype of severe twitching move- and genetics; (4) RNAi applications in DS research, especially ments, and then separately injecting single-stranded RNA (ss- recent (June 2006) breakthrough studies in DS pathways; and RNA) and double-stranded RNA (dsRNA) into the C. elegans (5) the potential of RNAi for R&D of future therapies for DS, gonad. The ssRNA injection (both sense and anti-sense types) and remaining challenges. failed to induce the predicted phenotype, however, injection of 4 DOWN SYNDROME QUARTERLY • VOLUME 9 • ISSUE 2 • MAY 2007 The Applications and Potential of RNA Interference for Down Syndrome Research and Therapy: Part I dsRNA not only caused the predicted phenotype, but
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