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.