Spotlight on Dr. Nakai

There are thousands of human genetic diseases that are often devastating and do not have effective treatment. Gene therapy holds promise for the treatment of many genetic diseases caused by a single gene defect; however, challenges remain in how to deliver therapeutic genes only to appropriate cells in patients efficiently and safely.

Hiroyuki Nakai, M.D., Ph.D., Associate Professor in the Department of Molecular and Medical Genetics has been studying adeno-associated virus (AAV) for 16 years to transform this virus into the most effective and safe therapeutic agent (i.e., vector) for gene therapy. AAV is the smallest DNA virus that does not cause any human diseases in natural infection. Many preclinical studies of AAV-mediated gene therapy have shown promising results, and safety and therapeutic efficacy have recently been demonstrated in several genetic diseases in human clinical trials. However, significant breakthroughs will still need to be made to broaden gene therapy applications for effective treatment of many genetic disorders and various acquired diseases. "Global gene delivery specifically to the target cells only in the target organ by putting the least amount of vector into the bloodstream is the most attractive approach in many gene therapy applications but it remains very challenging," said Dr. Nakai. 

In the last decade, a number of new AAV serotypes and variants have been discovered. Studies have shown that each serotype or variant exhibits its unique biological behavior when made into vectors. "We now know that we can significantly alter organ and cell tropism and other biological properties of AAV vectors by changing amino acid sequences of the viral coat protein called capsid, but we still do not know how we modify amino acids to obtain a desired phenotype. We have always wanted to figure out the amino acid sequence rule behind the biological properties of AAV, but it is so puzzling to understand by conventional approaches," he said. 

Now Dr. Nakai has an innovative research tool to begin to decipher the rule that governs the biological properties of AAV. His research team has invented a method called "AAV Barcode-Seq", which allows comprehensive biological analyses of the AAV viral coat in an unprecedentedly high-throughput manner, generating massive volumes of amino acid sequence-phenotype relationship data in test tubes, cultured cells, and experimental animals from mice to monkeys. The method uses emerging DNA barcording and massive parallel sequencing technologies and takes advantage of the concept of systems biology. The first set of the "AAV Barcode-Seq" data on structural and functional significance of the 381 amino acids in the C-terminal half of the AAV serotype 9 capsid will be presented at the American Society of Gene and Cell Therapy Meeting in May 2012. "This new study has just begun but we are confident that in collaboration with investigators in various disciplines our new approach holds enormous potential for studying the biology of gene delivery vectors and provides intellectual basis for developing novel vectors with the most desirable biological properties for clinical translation," said Dr. Nakai.

Dr. Nakai, born and grown up in Kyoto, Japan, spent 9 years in clinical practice before transitioning into the basic research on gene therapy in 1996.  He is the recipient of American Society of Gene and Cell Therapy Outstanding New Investigator Award 2011.