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
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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 communicationsExpression of a Secretable, Cell-Penetrating CDKL5 Protein Enhances the Efficacy of Gene Therapy for CDKL5 Deficiency Disorder
NeurotherapeuticsMulticolor labeling of airway neurons and analysis of parasympathetic heterogeneity
Scientific ReportsAdeno-associated virus-binding antibodies detected in cats living in the Northeastern United States lack neutralizing activity
Scientific ReportsIn Vivo Repair of a Protein Underlying a Neurological Disorder by Programmable RNA Editing
Cell ReportsCodon-Optimization of Wild-Type Adeno-Associated Virus Capsid Sequences Enhances DNA Family Shuffling while Conserving Functionality
Molecular Therapy Methods and Clinical DevelopmentA quantitative dot blot assay for AAV titration and its use for functional assessment of the adeno-associated virus assembly-activating proteins
Journal of Visualized ExperimentsAdeno-associated virus (AAV) assembly-activating protein is not an essential requirement for capsid assembly of AAV serotypes 4, 5, and 11
Journal of virologyEngineering a gene silencing viral construct that targets the cat hypothalamus to induce permanent sterility
Reproduction in Domestic AnimalsSite-directed RNA repair of endogenous Mecp2 RNA in neurons
Proceedings of the National Academy of Sciences of the United States of AmericaIdentification and characterization of nuclear and nucleolar localization signals in the adeno-associated virus serotype 2 assembly-activating protein
Journal of virologyDrawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing
Nature communicationsAn Experimental and Computational Evolution-Based Method to Study a Mode of Co-evolution of Overlapping Open Reading Frames in the AAV2 Viral Genome
PloS oneIntraganglionic AAV6 Results in Efficient and Long-Term Gene Transfer to Peripheral Sensory Nervous System in Adult Rats
PloS oneAAV vectors containing rDNA homology display increased chromosomal integration and transgene persistence
Molecular TherapyAdeno-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 MedicineA potential role of distinctively delayed blood clearance of recombinant adeno-associated virus serotype 9 in robust cardiac transduction
Molecular TherapyDirect injection into the dorsal root ganglion
Journal of Neuroscience MethodsA new recombinant adeno-associated virus (AAV)-based random peptide display library system
Gene Therapy and RegulationCharacterization of genome integrity for oversized recombinant AAV vector
Molecular TherapyEffects of irradiating adult mdx mice before full-length dystrophin cDNA transfer on host anti-dystrophin immunity
Gene therapyRapidly evolving adeno-associated virus vectors
Drug Delivery SystemEfficient and Durable Gene Transfer to Transplanted Heart Using Adeno-associated Virus 9 Vector
Journal of Heart and Lung TransplantationFrequency and spectrum of genomic integration of recombinant adeno-associated virus serotype 8 vector in neonatal mouse liver
Journal of virologyRecombinant adeno-associated virus type 8-mediated extensive therapeutic gene delivery into skeletal muscle of α-sarcoglycan-deficient mice
Human Gene TherapyThe host response to adenovirus, helper-dependent adenovirus, and adeno-associated virus in mouse liver
Molecular TherapyDNA 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 virologyThe role of DNA-PKcs and artemis in opening viral DNA hairpin termini in various tissues in mice
Journal of virology