Graduate Studies Faculty

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

Admin Unit: SOM-Molecular & Medical Genetics Department
Phone: 503-494-2256
Lab Phone: 503-494-9901
Fax: 503-494-6886
Office: RJH4598
Mail Code: L103
Molecular & Medical Genetics
Molecular Microbiology & Immunology
Program in Molecular & Cellular Biosciences
Research Interests:
Gene therapy, cell therapy, adeno-associated virus (AAV), virus structural biology, viral genome biology, genetic engineering, molecular therapy for genetic and acquired diseases, DNA damage and repair, genome instability, carcinogenesis, neurodegenerative disorders, reprogramming, bioinformatics, biostatistics, high performance computing, evolutionary computation, computer simulation, computational biology. » Click here for more about Dr. Nakai's research » PubMed Listing
Preceptor Rotations
Academic Term Available Summer 2017 Yes Fall 2017 Yes Winter 2017 Yes Winter 2018 Yes Spring 2018 Yes Summer 2018 Yes Fall 2018 Yes
Faculty Mentorship
Dr. Nakai is available as a mentor for 2017-2018.


Dr. Nakai received his M.D. from Kyoto Prefectural University of Medicine, Japan in 1987. After receiving his Ph.D. in hematology-oncology in 1994, Dr. Nakai joined Avigen Inc., California, to develop recombinant adeno-associated virus (rAAV) 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 rAAV 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 at the University of Pittsburgh School of Medicine as Assistant Professor. In the Summer of 2011, he joined the Department of Molecular and Medical Genetics, OHSU, as Associate Professor. Dr. Nakai is currently Professor of Molecular and Medical Genetics.


(1) Our research goals

The ultimate goals of our research are to completely elucidate the biology of AAV and cellular biology associated with AAV vector infection/transduction, and to develop new AAV vector-mediated gene and cell therapy approaches to successfully treat various human diseases. Despite the popularity and structural simplicity, the biology of AAV as a gene delivery vector is not well understood. Therefore, more profound understanding of the AAV biology and host responses is essential for improving the current approaches and establishing novel and more effective therapies. In addition, the study of AAV provides important clues to understanding various fundamental biological processes such as DNA damage responses and repair, DNA recombination and intra-, inter- and trans-cellular transport of biological molecules. Further more, AAV technology offers an unprecedented tool for studying pathogenesis of diseases. We are particularly interested in liver, heart and central nervous system (CNS) diseases and diabetes. 

(2) Adeno-associated virus

AAV is a non-pathogenic single-stranded DNA virus with the simplest viral structure and offers a promising and powerful tool for gene delivery. AAV vectors have been used in human clinical trials for gene therapy of genetic diseases including hemophilia, muscular dystrophies and retinal regeneration and acquired diseases such as Parkinson's disease, showing promise. However, issues remain to be overcome to make rAAV 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 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 pre-existing anti-AAV neutralizing antibodies in humans; and (5) a potential risk of AAV-mediated insertional mutagenesis causing malignancy. The challenge in our laboratory has been to overcome these issues toward successful rAAV-mediated human gene and cell therapies by substantially understanding the rAAV vector biology and host responses. 

(3) Ongoing Projects

In our laboratory, we have been studying AAV genome biology for many years. In this project, we focus on the interactions between viral genomes, host chromosomal DNA and host cellular DNA repair machinery in the in vivo context of various tissues to understand the post-uncoating events in AAV vector transduction. The AAV capsid biology project is aimed at mechanistically understanding how biological properties (i.e., phenotypes) of different types of AAV capsids are determined based on their capsid amino acid sequences. The phenotypes differ significantly between different AAV serotypes, naturally occurring subtypes and capsid-engineered artificial variants. These phenotypes include tropism, transduction efficiency, blood clearance rates, vascular permeability, antigenicity, immunogenicity, trafficking efficiency of viral particles (i.e., cell attachment, internalization, cytoplasmic and nuclear transport), virion uncoating rates, and so on. Many of these phenotypes have a significant impact on the outcomes of gene transfer. In this project, we address mechanisms and systems underlying a wide variety of combinations of viral phenotypes by taking multidisciplinary approaches that combine contemporary protein engineering, massively parallel sequencing, high performance computing, evolutionary computing, bioinformatics and biostatistics, as well as conventional molecular and cellular biology approaches. With a wealth of knowledge about the AAV genome and capsid biology gained in our research, we will be able to successfully translate gene and cell therapy approaches into the clinic. In the AAV capsid assembly project, we study the interactions between viral proteins and host nucleolar proteins during the AAV capsid assembly process. The knowledge obtained in this project not only furthers our understanding of AAV capsid assembly but also can be exploited to establish an improved rAAV vector production system. In our AAV translational preclinical research, our laboratory has established collaboration with investigators at the Oregon Stem Cell Center and the Oregon National Primate Research Center and initiated a series of projects that focus on gene therapy for CNS diseases, gene therapy for diabetes by cell fate conversion, and reproduction control by means of gene delivery.

Most recent publications

Earley, L.F., Powers, J.M, Adachi, K., Baumgart, J., Meyer, N.L., Xie, Q., Chapman, M.S., Nakai, H. 2017 "Adeno-associated virus assembly-activating protein is not an essential requirement for capsid assembly of AAV serotypes 4, 5 and 11" J. Virol. 91:e01980-16

Dissen, G.A., Lomniczi, A., Adachi, K., Chatkupt, T., Davidson, B.L., Nakai, H., Ojeda, S.R. 2017 "Engineering a Gene Silencing Viral Construct that Targets the Cat Hypothalamus to Induce Permanent Sterility: An Update" Reproduction in Domestic Animals Suppl 2:354-358. 

Earley, L.F., Kawano, Y., Adachi, K., Sun, X.X., Dai, M. S., Nakai, H. 2015 "Identification and characterization of nuclear and nucleolar localization signals in the adeno-associated virus serotype 2 assembly-activating protein" J. Virol. 89:3038-48 (highlighted in the Journal's Spotlight)

Adachi, K., Enoki, T., Kawano, Y., Veraz, M., Nakai, H. 2014 "Drawing a high-resolution functional map of adeno-associated virus capsid by massively parallel sequencing" Nat. Commun. 5:3075.