Hiroyuki Nakai, M.D., Ph.D.

  • Professor of Molecular and Medical Genetics, School of Medicine
  • Professor of Molecular Microbiology and Immunology, School of Medicine
  • School of Medicine Distinguished Professor in Molecular Medicine, Molecular and Medical Genetics, School of Medicine
  • Molecular and Medical Genetics Graduate Program, School of Medicine
  • Molecular Microbiology and Immunology Graduate Program, School of Medicine
  • Program in Molecular and Cellular Biosciences, School of Medicine
  • Neuroscience Graduate Program, School of Medicine
  • Oregon National Primate Research Center

Biography

BIOGRAPHY

Dr. Nakai received his M.D. from Kyoto Prefectural University of Medicine, Kyoto, Japan, in 1987. After completing his clinical residency and fellowship in Internal Medicine and receiving his Ph.D. in hematology-oncology in 1994, Dr. Nakai joined Avigen Inc., California, to develop recombinant adeno-associated virus (AAV) vectors for hemophilia gene therapy. In 1998, he joined Dr. Mark A. Kay's laboratory in the Departments of Pediatrics and Genetics, Stanford University School of Medicine, and studied the biology of AAV vectors in animals as a Postdoctoral Fellow and subsequently as a Senior Research Scientist. In 2005, Dr. Nakai joined the faculty in the Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine. In 2011, Dr. Nakai moved his lab to Oregon Health & Science University (OHSU) and joined the faculty in the Department of Molecular and Medical Genetics (MMG), OHSU. Dr. Nakai is currently Professor of Molecular and Medical Genetics (MMG) and Molecular Microbiology and Immunology (MMI) and Senior Scientist in the Division of Neuroscience, Oregon National Primate Research Center (ONPRC). Dr. Nakai has been studying AAV vectors and gene therapy for more than 20 years.

RESEARCH

The major goals of our laboratory are to comprehensively understand the biology of recombinant AAV vectors and the vector-host interactions and to develop new AAV vector-mediated gene and cell therapies to treat various human diseases. To achieve these goals, we take multi-disciplinary approaches in which we use molecular, cellular and structural biology techniques, bioinformatics, computational biology, computer simulation, various high-throughput technologies including DNA and RNA barcoding, the next-generation sequencing (NGS), and mass spectrometry. We study AAV in test tubes, in tissue culture cells, and in animals of various species, both small and large animals. Our laboratory is a part of the Oregon National Primate Research Center (ONPRC) and has been productively conducting AAV vector research using non-human primates. In addition, our high performance computing projects have been supported by the Pittsburgh Supercomputing Center for many years.

AAV is a non-pathogenic single-stranded DNA virus with the simplest viral structure. Recent studies have shown that single intravenous injection of AAV serotype 9 (AAV9) and novel AAV variant vectors into experimental animals can efficiently and safely deliver genetic payloads to many types of cells in the body, including the liver, heart, muscle and brain cells. Therefore, AAV vectors have gained an increasing attention as promising gene delivery vehicle for human gene therapy. However, various issues still need to be overcome to make AAV gene therapy successful and broaden its application to a variety of human diseases. The issues include: (1) the presence of many extracellular and intracellular barriers (physical and biological) that hinder efficient gene delivery to target cells/tissues, necessitating administration of high vector doses for clinically beneficial outcomes; (2) substantial vector spillover to non-target cells/tissues at therapeutically effective vector doses due to promiscuous viral tropism; (3) efficacy-limiting host immune responses against viral proteins; (4) the high prevalence of preexisting anti-AAV neutralizing antibodies in humans; (5) difficulty in production of high titer AAV vectors; and (6) a potential risk of AAV vector-mediated insertional mutagenesis causing malignancy. Our laboratory has been tackling these challenges by seeking to substantially understand the AAV vector biology and host responses, and trying to establish novel methods and technologies to overcome the challenges toward successful AAV vector-mediated human gene and cell therapies. Thus, the basic biology of AAV and its translational application are both the subjects of our research. Despite the structural simplicity, the biology of this virus is very complicated and is not well understood, and studying viruses and virus-host interactions often provides more-than-anticipated novel insights into fundamental biological processes in living organisms, which all have been and will be continuing to fascinate us.

Education and training

  • Degrees

    • M.D., 1987, Kyoto Prefectural University of Medicine
    • Ph.D., 1994, Kyoto Prefectural University of Medicine

Publications

Publications

  • Enhancing gene transfer to renal tubules and podocytes by context-dependent selection of AAV capsids

    Nature communications
    1. Taisuke Furusho
    2. Ranjan Das
    3. Hideyuki Hakui
    4. Anusha Sairavi
    5. Kei Adachi
    6. Mia S. Galbraith-Liss
    7. Pratheppa Rajagopal
    8. Masahiro Horikawa
    9. Shuhua Luo
    10. Lena Li
    11. Kentaro Yamada
    12. Nicole Andeen
    13. Gregory Dissen
    14. Hiroyuki Nakai
  • Expression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder

    Neurotherapeutics
    1. Giorgio Medici
    2. Marianna Tassinari
    3. Giuseppe Galvani
    4. Stefano Bastianini
    5. Laura Gennaccaro
    6. Manuela Loi
    7. Nicola Mottolese
    8. Sara Alvente
    9. Chiara Berteotti
    10. Giulia Sagona
    11. Leonardo Lupori
    12. Giulia Candini
    13. Helen Rappe Baggett
    14. Giovanna Zoccoli
    15. Maurizio Giustetto
    16. Alysson Muotri
    17. Tommaso Pizzorusso
    18. Hiroyuki Nakai
    19. Stefania Trazzi
    20. Elisabetta Ciani
  • Multicolor labeling of airway neurons and analysis of parasympathetic heterogeneity

    Scientific Reports
    1. Alexandra B. Pincus
    2. Samuel J. Huang
    3. Katie M. Lebold
    4. Ubaldo De La Torre
    5. Becky J. Proskocil
    6. Matthew G. Drake
    7. Hiroyuki Nakai
    8. Allison D. Fryer
    9. David B. Jacoby
  • Adeno-associated virus-binding antibodies detected in cats living in the Northeastern United States lack neutralizing activity

    Scientific Reports
    1. Kei Adachi
    2. Gregory A. Dissen
    3. Alejandro Lomniczi
    4. Qing Xie
    5. Sergio R. Ojeda
    6. Hiroyuki Nakai
  • In Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing

    Cell Reports
    1. John R. Sinnamon
    2. Susan Y. Kim
    3. Jenna R. Fisk
    4. Zhen Song
    5. Hiroyuki Nakai
    6. Sophia Jeng
    7. Shannon K. McWeeney
    8. Gail Mandel
  • Codon-Optimization of Wild-Type Adeno-Associated Virus Capsid Sequences Enhances DNA Family Shuffling while Conserving Functionality

    Molecular Therapy Methods and Clinical Development
    1. Marti Cabanes-Creus
    2. Samantha L. Ginn
    3. Anais K. Amaya
    4. Sophia H.Y. Liao
    5. Adrian Westhaus
    6. Claus V. Hallwirth
    7. Patrick Wilmott
    8. Jason Ward
    9. Kimberley L. Dilworth
    10. Giorgia Santilli
    11. Arkadiusz Rybicki
    12. Hiroyuki Nakai
    13. Adrian J. Thrasher
    14. Adrian C. Filip
    15. Ian E. Alexander
    16. Leszek Lisowski
  • A quantitative dot blot assay for AAV titration and its use for functional assessment of the adeno-associated virus assembly-activating proteins

    Journal of Visualized Experiments
    1. John M. Powers
    2. Xiao Lan Chang
    3. Zhen Song
    4. Hiroyuki Nakai
  • Adeno-associated virus (AAV) assembly-activating protein is not an essential requirement for capsid assembly of AAV serotypes 4, 5, and 11

    Journal of virology
    1. Lauriel F. Earley
    2. John M. Powers
    3. Kei Adachi
    4. Joshua T. Baumgart
    5. Nancy L. Meyer
    6. Qing Xie
    7. Michael S. Chapman
    8. Hiroyuki Nakai
  • Engineering a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility

    Reproduction in Domestic Animals
    1. G. A. Dissen
    2. K. Adachi
    3. A. Lomniczi
    4. T. Chatkupt
    5. B. L. Davidson
    6. H. Nakai
    7. S. R. Ojeda
  • Site-directed RNA repair of endogenous Mecp2 RNA in neurons

    Proceedings of the National Academy of Sciences of the United States of America
    1. John R. Sinnamon
    2. Susan Y. Kim
    3. Glen M. Corson
    4. Zhen Song
    5. Hiroyuki Nakai
    6. John P. Adelman
    7. Gail Mandel
  • Identification and characterization of nuclear and nucleolar localization signals in the adeno-associated virus serotype 2 assembly-activating protein

    Journal of virology
    1. Lauriel F. Earley
    2. Yasuhiro Kawano
    3. Kei Adachi
    4. Xiao Xin Sun
    5. Mu Shui Dai
    6. Hiroyuki Nakai
  • Drawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing

    Nature communications
    1. Kei Adachi
    2. Tatsuji Enoki
    3. Yasuhiro Kawano
    4. Michael Veraz
    5. Hiroyuki Nakai
  • An Experimental and Computational Evolution-Based Method to Study a Mode of Co-evolution of Overlapping Open Reading Frames in the AAV2 Viral Genome

    PloS one
    1. Yasuhiro Kawano
    2. Shane Neeley
    3. Kei Adachi
    4. Hiroyuki Nakai
  • Intraganglionic AAV6 Results in Efficient and Long-Term Gene Transfer to Peripheral Sensory Nervous System in Adult Rats

    PloS one
    1. Hongwei Yu
    2. Gregory Fischer
    3. Lejla Ferhatovic
    4. Fan Fan
    5. Alan R. Light
    6. Dorothee Weihrauch
    7. Damir Sapunar
    8. Hiroyuki Nakai
    9. Frank Park
    10. Quinn H. Hogan
  • AAV vectors containing rDNA homology display increased chromosomal integration and transgene persistence

    Molecular Therapy
    1. Zhongya Wang
    2. Leszek Lisowski
    3. Milton J. Finegold
    4. Hiroyuki Nakai
    5. Mark A. Kay
    6. Markus Grompe
  • Adeno-associated virus serotype 8 (AAV8) delivery of recombinant A20 to skeletal muscle reduces pathological Activation of Nuclear Factor (NF)-κB in muscle of mdx mice

    Molecular Medicine
    1. Rakshita A. Charan
    2. Gabriela Niizawa
    3. Hiroyuki Nakai
    4. Paula R. Clemens
  • A potential role of distinctively delayed blood clearance of recombinant adeno-associated virus serotype 9 in robust cardiac transduction

    Molecular Therapy
    1. Nicole M. Kotchey
    2. Kei Adachi
    3. Maliha Zahid
    4. Katsuya Inagaki
    5. Rakshita Charan
    6. Robert S. Parker
    7. Hiroyuki Nakai
  • Direct injection into the dorsal root ganglion

    Journal of Neuroscience Methods
    1. Gregory Fischer
    2. Sandra Kostic
    3. Hiroyuki Nakai
    4. Frank Park
    5. Damir Sapunar
    6. Hongwei Yu
    7. Quinn Hogan
  • A new recombinant adeno-associated virus (AAV)-based random peptide display library system

    Gene Therapy and Regulation
    1. Kei Adachi
    2. Hiroyuki Nakai
  • Characterization of genome integrity for oversized recombinant AAV vector

    Molecular Therapy
    1. Biao Dong
    2. Hiroyuki Nakai
    3. Weidong Xiao
  • Effects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity

    Gene therapy
    1. S. Eghtesad
    2. H. Zheng
    3. H. Nakai
    4. M. W. Epperly
    5. P. R. Clemens
  • Rapidly evolving adeno-associated virus vectors

    Drug Delivery System
    1. Hiroyuki Nakai
  • Efficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector

    Journal of Heart and Lung Transplantation
    1. Naoto Miyagi
    2. Vinay P. Rao
    3. Davide Ricci
    4. Zeji Du
    5. Guerard W. Byrne
    6. Kent R. Bailey
    7. Hiroyuki Nakai
    8. Stephen J. Russell
    9. Christopher G.A. McGregor
  • Frequency and spectrum of genomic integration of recombinant adeno-associated virus serotype 8 vector in neonatal mouse liver

    Journal of virology
    1. Katsuya Inagaki
    2. Chuncheng Piao
    3. Nicole M. Kotchey
    4. Xiaolin Wu
    5. Hiroyuki Nakai
  • Recombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice

    Human Gene Therapy
    1. Akiyo Nishiyama
    2. Beryl Nyamekye Ampong
    3. Sachiko Ohshima
    4. Jin Hong Shin
    5. Hiroyuki Nakai
    6. Michihiro Imamura
    7. Yuko Miyagoe-Suzuki
    8. Takashi Okada
    9. Shin'ichi Takeda
  • The host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver

    Molecular Therapy
    1. Anton P. McCaffrey
    2. Paul Fawcett
    3. Hiroyuki Nakai
    4. Ramona L. McCaffrey
    5. Anja Ehrhardt
    6. Thu Thao T. Pham
    7. Kusum Pandey
    8. Hui Xu
    9. Sally Feuss
    10. Theresa A. Storm
    11. Mark A. Kay
  • DNA palindromes with a modest arm length of ≳20 base pairs are a significant target for recombinant adeno-associated virus vector integration in the liver, muscles, and heart in mice

    Journal of virology
    1. Katsuya Inagaki
    2. Susanna M. Lewis
    3. Xiaolin Wu
    4. Congrong Ma
    5. David J. Munroe
    6. Sally Fuess
    7. Theresa A. Storm
    8. Mark A. Kay
    9. Hiroyuki Nakai
  • The role of DNA-PKcs and artemis in opening viral DNA hairpin termini in various tissues in mice

    Journal of virology
    1. Katsuya Inagaki
    2. Congrong Ma
    3. Theresa A. Storm
    4. Mark A. Kay
    5. Hiroyuki Nakai