Volume 25 Issue 2, February 2019

Volume 25 Issue 2

Restoring vision loss

Photoreceptor ciliopathies constitute the most common molecular mechanism of the childhood blindness Leber congenital amaurosis. In this issue of Nature Medicine, Artur Cideciyan and colleagues report that RNA antisense oligonucleotide therapy restores normal splicing of a ciliopathy-associated gene and shows promising safety and efficacy results in patients with Leber’s amaurosis. In an independent study, Morgan Maeder and colleagues report the development of a gene-editing approach to restore vision in preclinical models of this disease.

See Cideciyan and colleagues, Maeder and colleagues and News & Views by Sahel and Dalkara

Image credit: cosmin4000/iStock/Getty Images Plus. Cover design: Erin Dewalt

Editorial

  • Editorial |

    As the world reckons with the news of the first use of genome editing in the human germline, researchers, clinicians, ethicists and policy makers must work across international boundaries to outline a transparent path forward for the responsible translation of this technology in the future.

News Feature

  • News Feature |

    Careful sorting of probiotics may finally pave the way for an FDA approval.

    • Shraddha Chakradhar

Turning Points

  • Turning Points |

    Kjersti Aagaard is a practicing maternal–fetal medicine obstetrician at Texas Children’s and Ben Taub Hospitals and a reproductive biologist at Baylor College of Medicine. She studies a myriad of aspects of the microbiome, including how it can influence pregnancy and the developing infant.

    • Kjersti Aagaard
  • Turning Points |

    Eran Elinav is an immunologist at the Weizmann Institute of Science in Rehovot, Israel. He has earned many distinctions, including being named a Howard Hughes Medical Institute and Bill and Melinda Gates Foundation research scholar in 2017.

    • Eran Elinav

Research Highlights

News & Views

  • News & Views |

    Counteracting splice defects in the CEP290 gene using RNA antisense oligonucleotides or Cas9-mediated gene editing is a therapeutic strategy for Leber congenital amaurosis type 10—a severe untreatable retinal dystrophy leading to childhood blindness.

    • José Alain Sahel
    •  & Deniz Dalkara
  • News & Views |

    Vaccination with the tuberculosis (TB) vaccine Bacillus Calmette–Guérin (BCG) into the lungs of Rhesus macaques induces specific, local immune responses that delay infection in some animals and completely prevent it in others while protecting against TB disease.

    • Thomas J. Scriba
    •  & Elisa Nemes
  • News & Views |

    Two new biomarkers for Alzheimer’s disease include one in the blood that relates to neurodegeneration and another that reflects blood–brain barrier dysfunction and is identifiable in cerebrospinal fluid analysis.

    • Henrik Zetterberg
    •  & Jonathan M. Schott
  • News & Views |

    Antitumor immunity can be enhanced by blocking NKG2A, an inhibitory receptor expressed on natural killer and T cells.

    • Matthew D. Hellmann
    •  & Alexandra Snyder

Perspectives

  • Perspective |

    The emerging field of precision epidemiology allows the personalized diagnosis, tracking and treatment of infectious diseases.

    • Jason T. Ladner
    • , Nathan D. Grubaugh
    • , Oliver G. Pybus
    •  & Kristian G. Andersen

Review Articles

  • Review Article |

    The universal flu vaccine remains elusive, but there are several strategies that scientists can take to develop one, including closer monitoring of viral evolution.

    • Seiya Yamayoshi
    •  & Yoshihiro Kawaoka

    Nature Outlook:

Brief Communications

  • Brief Communication |

    Mutational signatures in melanoma are associated with prognostic features in patients and suggest distinct disease etiologies associated with the influence of different wavelengths of ultraviolet radiation.

    • Lucas D. Trucco
    • , Piyushkumar A. Mundra
    • , Kate Hogan
    • , Pablo Garcia-Martinez
    • , Amaya Viros
    • , Amit K. Mandal
    • , Nicolas Macagno
    • , Caroline Gaudy-Marqueste
    • , Donald Allan
    • , Franziska Baenke
    • , Martin Cook
    • , Clare McManus
    • , Berta Sanchez-Laorden
    • , Nathalie Dhomen
    •  & Richard Marais
  • Brief Communication |

    RNA antisense oligonucleotide therapy to restore normal splicing of a ciliopathy gene shows promising safety and efficacy results in a clinical trial to treat a form of childhood blindness.

    • Artur V. Cideciyan
    • , Samuel G. Jacobson
    • , Arlene V. Drack
    • , Allen C. Ho
    • , Jason Charng
    • , Alexandra V. Garafalo
    • , Alejandro J. Roman
    • , Alexander Sumaroka
    • , Ian C. Han
    • , Maria D. Hochstedler
    • , Wanda L. Pfeifer
    • , Elliott H. Sohn
    • , Magali Taiel
    • , Michael R. Schwartz
    • , Patricia Biasutto
    • , Wilma de Wit
    • , Michael E. Cheetham
    • , Peter Adamson
    • , David M. Rodman
    • , Gerard Platenburg
    • , Maria D. Tome
    • , Irina Balikova
    • , Fanny Nerinckx
    • , Julie De Zaeytijd
    • , Caroline Van Cauwenbergh
    • , Bart P. Leroy
    •  & Stephen R. Russell

    Nature Outlook:

Letters

  • Letter |

    In human cells, a humanized mouse model and non-human primates, CRISPR/Cas9 corrects the splicing defect in a gene associated with congenital blindness.

    • Morgan L. Maeder
    • , Michael Stefanidakis
    • , Christopher J. Wilson
    • , Reshica Baral
    • , Luis Alberto Barrera
    • , George S. Bounoutas
    • , David Bumcrot
    • , Hoson Chao
    • , Dawn M. Ciulla
    • , Jennifer A. DaSilva
    • , Abhishek Dass
    • , Vidya Dhanapal
    • , Tim J. Fennell
    • , Ari E. Friedland
    • , Georgia Giannoukos
    • , Sebastian W. Gloskowski
    • , Alexandra Glucksmann
    • , Gregory M. Gotta
    • , Hariharan Jayaram
    • , Scott J. Haskett
    • , Bei Hopkins
    • , Joy E. Horng
    • , Shivangi Joshi
    • , Eugenio Marco
    • , Rina Mepani
    • , Deepak Reyon
    • , Terence Ta
    • , Diana G. Tabbaa
    • , Steven J. Samuelsson
    • , Shen Shen
    • , Maxwell N. Skor
    • , Pam Stetkiewicz
    • , Tongyao Wang
    • , Clifford Yudkoff
    • , Vic E. Myer
    • , Charles F. Albright
    •  & Haiyan Jiang
  • Letter |

    In a phase 1/2 clinical trial, gene therapy with autologous hematopoietic stem cells significantly reduced transfusion requirement in adults and children with transfusion dependent ß-thalassemia.

    • Sarah Marktel
    • , Samantha Scaramuzza
    • , Maria Pia Cicalese
    • , Fabio Giglio
    • , Stefania Galimberti
    • , Maria Rosa Lidonnici
    • , Valeria Calbi
    • , Andrea Assanelli
    • , Maria Ester Bernardo
    • , Claudia Rossi
    • , Andrea Calabria
    • , Raffaella Milani
    • , Salvatore Gattillo
    • , Fabrizio Benedicenti
    • , Giulio Spinozzi
    • , Annamaria Aprile
    • , Alessandra Bergami
    • , Miriam Casiraghi
    • , Giulia Consiglieri
    • , Nicoletta Masera
    • , Emanuela D’Angelo
    • , Nadia Mirra
    • , Raffaella Origa
    • , Immacolata Tartaglione
    • , Silverio Perrotta
    • , Robert Winter
    • , Milena Coppola
    • , Gianluca Viarengo
    • , Luca Santoleri
    • , Giovanna Graziadei
    • , Michela Gabaldo
    • , Maria Grazia Valsecchi
    • , Eugenio Montini
    • , Luigi Naldini
    • , Maria Domenica Cappellini
    • , Fabio Ciceri
    • , Alessandro Aiuti
    •  & Giuliana Ferrari
  • Letter |

    Cas9-specific antibodies and reactive T cells are found in the majority of healthy adult human serum samples analyzed. Such preexisting adaptive immunity should be taken into consideration as the CRISPR–Cas9 system moves toward clinical trials.

    • Carsten T. Charlesworth
    • , Priyanka S. Deshpande
    • , Daniel P. Dever
    • , Joab Camarena
    • , Viktor T. Lemgart
    • , M. Kyle Cromer
    • , Christopher A. Vakulskas
    • , Michael A. Collingwood
    • , Liyang Zhang
    • , Nicole M. Bode
    • , Mark A. Behlke
    • , Beruh Dejene
    • , Brandon Cieniewicz
    • , Rosa Romano
    • , Benjamin J. Lesch
    • , Natalia Gomez-Ospina
    • , Sruthi Mantri
    • , Mara Pavel-Dinu
    • , Kenneth I. Weinberg
    •  & Matthew H. Porteus
  • Letter |

    Delivery of the Bacillus Calmette–Guérin vaccine into the lungs but not the skin of rhesus macaques protects animals from infection with Mycobacterium tuberculosis, suggesting that immune responses elicited locally may be required for vaccine efficacy.

    • Karin Dijkman
    • , Claudia C. Sombroek
    • , Richard A. W. Vervenne
    • , Sam O. Hofman
    • , Charelle Boot
    • , Edmond J. Remarque
    • , Clemens H. M. Kocken
    • , Tom H. M. Ottenhoff
    • , Ivanela Kondova
    • , Mohammed A. Khayum
    • , Krista G. Haanstra
    • , Michel P. M. Vierboom
    •  & Frank A. W. Verreck
  • Letter |

    Fast scalable 3D bioprinting generates biocompatible and biomimetic scaffolds to precisely fit the geometries of spinal cord lesions, promote axonal regeneration, and support stem cell grafts to promote recovery from spinal cord injury in rodents.

    • Jacob Koffler
    • , Wei Zhu
    • , Xin Qu
    • , Oleksandr Platoshyn
    • , Jennifer N. Dulin
    • , John Brock
    • , Lori Graham
    • , Paul Lu
    • , Jeff Sakamoto
    • , Martin Marsala
    • , Shaochen Chen
    •  & Mark H. Tuszynski
  • Letter |

    Neuroimaging and cerebrospinal fluid analyses in humans reveal that loss of blood–brain barrier integrity and brain capillary pericyte damage are early biomarkers of cognitive impairment that occur independently of changes in amyloid-β and tau.

    • Daniel A. Nation
    • , Melanie D. Sweeney
    • , Axel Montagne
    • , Abhay P. Sagare
    • , Lina M. D’Orazio
    • , Maricarmen Pachicano
    • , Farshid Sepehrband
    • , Amy R. Nelson
    • , David P. Buennagel
    • , Michael G. Harrington
    • , Tammie L. S. Benzinger
    • , Anne M. Fagan
    • , John M. Ringman
    • , Lon S. Schneider
    • , John C. Morris
    • , Helena C. Chui
    • , Meng Law
    • , Arthur W. Toga
    •  & Berislav V. Zlokovic
  • Letter |

    In a longitudinal cohort of familial Alzheimer’s disease patients, the rate of change of blood biomarker levels identifies disease carriers much earlier than absolute levels and predicts both neurodegeneration and cognitive decline.

    • Oliver Preische
    • , Stephanie A. Schultz
    • , Anja Apel
    • , Jens Kuhle
    • , Stephan A. Kaeser
    • , Christian Barro
    • , Susanne Gräber
    • , Elke Kuder-Buletta
    • , Christian LaFougere
    • , Christoph Laske
    • , Jonathan Vöglein
    • , Johannes Levin
    • , Colin L. Masters
    • , Ralph Martins
    • , Peter R. Schofield
    • , Martin N. Rossor
    • , Neill R. Graff-Radford
    • , Stephen Salloway
    • , Bernardino Ghetti
    • , John M. Ringman
    • , James M. Noble
    • , Jasmeer Chhatwal
    • , Alison M. Goate
    • , Tammie L. S. Benzinger
    • , John C. Morris
    • , Randall J. Bateman
    • , Guoqiao Wang
    • , Anne M. Fagan
    • , Eric M. McDade
    • , Brian A. Gordon
    • , Mathias Jucker
    • , Ricardo Allegri
    • , Fatima Amtashar
    • , Randall Bateman
    • , Tammie Benzinger
    • , Sarah Berman
    • , Courtney Bodge
    • , Susan Brandon
    • , William Brooks
    • , Jill Buck
    • , Virginia Buckles
    • , Sochenda Chea
    • , Jasmeer Chhatwal
    • , Patricio Chrem
    • , Helena Chui
    • , Jake Cinco
    • , Jack Clifford
    • , Carlos Cruchaga
    • , Mirelle D’Mello
    • , Tamara Donahue
    • , Jane Douglas
    • , Noelia Edigo
    • , Nilufer Erekin-Taner
    • , Anne Fagan
    • , Marty Farlow
    • , Angela Farrar
    • , Howard Feldman
    • , Gigi Flynn
    • , Nick Fox
    • , Erin Franklin
    • , Hisako Fujii
    • , Cortaiga Gant
    • , Samantha Gardener
    • , Bernardino Ghetti
    • , Alison Goate
    • , Jill Goldman
    • , Brian Gordon
    • , Neill Graff-Radford
    • , Julia Gray
    • , Jenny Gurney
    • , Jason Hassenstab
    • , Mie Hirohara
    • , David Holtzman
    • , Russ Hornbeck
    • , Siri Houeland DiBari
    • , Takeshi Ikeuchi
    • , Snezana Ikonomovic
    • , Gina Jerome
    • , Mathias Jucker
    • , Celeste Karch
    • , Kensaku Kasuga
    • , Takeshi Kawarabayashi
    • , William Klunk
    • , Robert Koeppe
    • , Elke Kuder-Buletta
    • , Christoph Laske
    • , Jae-Hong Lee
    • , Johannes Levin
    • , Daniel Marcus
    • , Ralph Martins
    • , Neal Scott Mason
    • , Colin Masters
    • , Denise Maue-Dreyfus
    • , Eric McDade
    • , Lucy Montoya
    • , Hiroshi Mori
    • , John Morris
    • , Akem Nagamatsu
    • , Katie Neimeyer
    • , James Noble
    • , Joanne Norton
    • , Richard Perrin
    • , Marc Raichle
    • , John Ringman
    • , Jee Hoon Roh
    • , Stephen Salloway
    • , Peter Schofield
    • , Hiroyuki Shimada
    • , Tomoyo Shiroto
    • , Mikio Shoji
    • , Wendy Sigurdson
    • , Hamid Sohrabi
    • , Paige Sparks
    • , Kazushi Suzuki
    • , Laura Swisher
    • , Kevin Taddei
    • , Jen Wang
    • , Peter Wang
    • , Mike Weiner
    • , Mary Wolfsberger
    • , Chengjie Xiong
    •  & Xiong Xu
  • Letter |

    The new RAF inhibitor PLX8394 selectively blocks ERK signaling in tumors driven by class 1 and/or class 2 BRAF mutations and BRAF fusions while maintaining a broad therapeutic window.

    • Zhan Yao
    • , Yijun Gao
    • , Wenjing Su
    • , Rona Yaeger
    • , Jessica Tao
    • , Na Na
    • , Ying Zhang
    • , Chao Zhang
    • , Andrey Rymar
    • , Anthony Tao
    • , Neilawattie M. Timaul
    • , Rory Mcgriskin
    • , Nathaniel A. Outmezguine
    • , HuiYong Zhao
    • , Qing Chang
    • , Besnik Qeriqi
    • , Mariano Barbacid
    • , Elisa de Stanchina
    • , David M Hyman
    • , Gideon Bollag
    •  & Neal Rosen
  • Letter |

    A combination of genome-scale CRISPR-Cas9 screening and focused small-molecule sensitivity profiling enables the discovery of therapeutically targetable tumor dependencies in rare tumors.

    • Tanaz Sharifnia
    • , Mathias J. Wawer
    • , Ting Chen
    • , Qing-Yuan Huang
    • , Barbara A. Weir
    • , Ann Sizemore
    • , Matthew A. Lawlor
    • , Amy Goodale
    • , Glenn S. Cowley
    • , Francisca Vazquez
    • , Christopher J. Ott
    • , Joshua M. Francis
    • , Slim Sassi
    • , Patricia Cogswell
    • , Hadley E. Sheppard
    • , Tinghu Zhang
    • , Nathanael S. Gray
    • , Paul A. Clarke
    • , Julian Blagg
    • , Paul Workman
    • , Josh Sommer
    • , Francis Hornicek
    • , David E. Root
    • , William C. Hahn
    • , James E. Bradner
    • , Kwok K. Wong
    • , Paul A. Clemons
    • , Charles Y. Lin
    • , Joanne D. Kotz
    •  & Stuart L. Schreiber

Articles

  • Article |

    Oncogene cooperation enhances PD-L1 translation to promote immune evasion and metastasis in a novel model of liver cancer.

    • Yichen Xu
    • , Mauro Poggio
    • , Hyun Yong Jin
    • , Zhen Shi
    • , Craig M. Forester
    • , Ying Wang
    • , Craig R. Stumpf
    • , Lingru Xue
    • , Emily Devericks
    • , Lomon So
    • , Hao G. Nguyen
    • , Alice Griselin
    • , John D. Gordan
    • , Sarah E Umetsu
    • , Siegfried H. Reich
    • , Stephen T. Worland
    • , Saurabh Asthana
    • , Maria Barna
    • , Kevin R. Webster
    • , John T. Cunningham
    •  & Davide Ruggero
  • Article |

    A disturbed microbial network characterizes relapsing refractory Crohn’s disease and antedates disease recurrence after surgical removal of the active disease segment.

    • Bahtiyar Yilmaz
    • , Pascal Juillerat
    • , Ove Øyås
    • , Charlotte Ramon
    • , Francisco Damian Bravo
    • , Yannick Franc
    • , Nicolas Fournier
    • , Pierre Michetti
    • , Christoph Mueller
    • , Markus Geuking
    • , Valerie E. H. Pittet
    • , Michel H. Maillard
    • , Gerhard Rogler
    • , Karim Abdelrahman
    • , Gentiana Ademi
    • , Patrick Aepli
    • , Amman Thomas
    • , Claudia Anderegg
    • , Anca-Teodora Antonino
    • , Eva Archanioti
    • , Eviano Arrigoni
    • , Diana Bakker de Jong
    • , Bruno Balsiger
    • , Polat Bastürk
    • , Peter Bauerfeind
    • , Andrea Becocci
    • , Dominique Belli
    • , José M. Bengoa
    • , Luc Biedermann
    • , Janek Binek
    • , Mirjam Blattmann
    • , Stephan Boehm
    • , Tujana Boldanova
    • , Jan Borovicka
    • , Christian P. Braegger
    • , Stephan Brand
    • , Lukas Brügger
    • , Simon Brunner
    • , Patrick Bühr
    • , Bernard Burnand
    • , Sabine Burk
    • , Emanuel Burri
    • , Sophie Buyse
    • , Dahlia-Thao Cao
    • , Ove Carstens
    • , Dominique H. Criblez
    • , Sophie Cunningham
    • , Fabrizia D’Angelo
    • , Philippe de Saussure
    • , Lukas Degen
    • , Joakim Delarive
    • , Christopher Doerig
    • , Barbara Dora
    • , Susan Drerup
    • , Mara Egger
    • , Ali El-Wafa
    • , Matthias Engelmann
    • , Jessica Ezri
    • , Christian Felley
    • , Markus Fliegner
    • , Nicolas Fournier
    • , Montserrat Fraga
    • , Yannick Franc
    • , Pascal Frei
    • , Remus Frei
    • , Michael Fried
    • , Florian Froehlich
    • , Raoul Ivano Furlano
    • , Luca Garzoni
    • , Martin Geyer
    • , Laurent Girard
    • , Marc Girardin
    • , Delphine Golay
    • , Ignaz Good
    • , Ulrike Graf Bigler
    • , Beat Gysi
    • , Johannes Haarer
    • , Marcel Halama
    • , Janine Haldemann
    • , Pius Heer
    • , Benjamin Heimgartner
    • , Beat Helbling
    • , Peter Hengstler
    • , Denise Herzog
    • , Cyrill Hess
    • , Roxane Hessler
    • , Klaas Heyland
    • , Thomas Hinterleitner
    • , Claudia Hirschi
    • , Petr Hruz
    • , Pascal Juillerat
    • , Carolina Khalid-de Bakker
    • , Stephan Kayser
    • , Céline Keller
    • , Christina Knellwolf (-Grieger)
    • , Christoph Knoblauch
    • , Henrik Köhler
    • , Rebekka Koller
    • , Claudia Krieger(-Grübel)
    • , Patrizia Künzler
    • , Rachel Kusche
    • , Frank Serge Lehmann
    • , Andrew J. Macpherson
    • , Michel H. Maillard
    • , Michael Manz
    • , Astrid Marot
    • , Rémy Meier
    • , Christa Meyenberger
    • , Pamela Meyer
    • , Pierre Michetti
    • , Benjamin Misselwitz
    • , Patrick Mosler
    • , Christian Mottet
    • , Christoph Müller
    • , Beat Müllhaupt
    • , Leilla Musso
    • , Michaela Neagu
    • , Cristina Nichita
    • , Jan Niess
    • , Andreas Nydegger
    • , Nicole Obialo
    • , Diana Ollo
    • , Cassandra Oropesa
    • , Ulrich Peter
    • , Daniel Peternac
    • , Laetitia Marie Petit
    • , Valérie Pittet
    • , Daniel Pohl
    • , Marc Porzner
    • , Claudia Preissler
    • , Nadia Raschle
    • , Ronald Rentsch
    • , Alexandre Restellini
    • , Sophie Restellini
    • , Jean-Pierre Richterich
    • , Frederic Ris
    • , Branislav Risti
    • , Marc Alain Ritz
    • , Gerhard Rogler
    • , Nina Röhrich
    • , Jean-Benoît Rossel
    • , Vanessa Rueger
    • , Monica Rusticeanu
    • , Markus Sagmeister
    • , Gaby Saner
    • , Bernhard Sauter
    • , Mikael Sawatzki
    • , Michael Scharl
    • , Martin Schelling
    • , Susanne Schibli
    • , Hugo Schlauri
    • , Dominique Schluckebier
    • , Daniela Schmid
    • , Sybille Schmid (-Uebelhart)
    • , Jean-François Schnegg
    • , Alain Schoepfer
    • , Vivianne Seematter
    • , Frank Seibold
    • , Mariam Seirafi
    • , Gian-Marco Semadeni
    • , Arne Senning
    • , Christiane Sokollik
    • , Joachim Sommer
    • , Johannes Spalinger
    • , Holger Spangenberger
    • , Philippe Stadler
    • , Peter Staub
    • , Dominic Staudenmann
    • , Volker Stenz
    • , Michael Steuerwald
    • , Alex Straumann
    • , Bruno Strebel
    • , Andreas Stulz
    • , Michael Sulz
    • , Aurora Tatu
    • , Michela Tempia-Caliera
    • , Joël Thorens
    • , Kaspar Truninger
    • , Radu Tutuian
    • , Patrick Urfer
    • , Stephan Vavricka
    • , Francesco Viani
    • , Jürg Vögtlin
    • , Roland Von Känel
    • , Dominique Vouillamoz
    • , Rachel Vulliamy
    • , Paul Wiesel
    • , Reiner Wiest
    • , Stefanie Wöhrle
    • , Samuel Zamora
    • , Silvan Zander
    • , Tina Wylie
    • , Jonas Zeitz
    • , Dorothee Zimmermann
    • , Reiner Wiest
    • , Jörg Stelling
    •  & Andrew J. Macpherson

Amendments & Corrections