Genome and Cellular Functions

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Professor: Hiroyuki Kugoh
Associate professor: Yasuhiro Kazuki
Assistant professor: Takahito Ohira
Assistant professor: Takashi Moriwaki
Assistant professor: Naomi Miyke

Features of the Division and Research Areas

(1) Gene therapy via human artificial chromosomes (HAC)
Human artificial chromosomes (HACs) exhibit several important characteristics that are important for an ideal gene delivery vector, including stable episomal maintenance and the capacity to carry large genomic loci with their regulatory elements. These characteristics allow the physiological regulation of the introduced gene in a manner similar to that of native chromosomes. We previously developed HAC vectors from normal human chromosomes using a chromosome engineering technique. Our current research goal is to develop new methods for gene therapy using recently developed HAC vectors.

1) Gene therapy for Duchenne muscular dystrophy
Duchenne muscular dystrophy (DMD) is caused by dysfunction of the dystrophin gene. Although several vectors have been developed for DMD gene therapy, no episomal vector containing the entire dystrophin genomic region has been reported, due to the extremely large size of the region (2.4 Mb). We have demonstrated the complete correction of a genetic deficiency in iPS cells derived from a DMD model (mdx) mice and a human DMD patient using a HAC with a complete genomic dystrophin sequence (DYS-HAC). Our next goal for developing gene therapy with DMD is to develop an efficient method of differentiation from iPS cells into muscle stem cells in vitro, and a transplantation method of genetically corrected autologous cells into the same patient.

2) Hemophilia
Hemophilia A is an X-linked recessive bleeding disorder caused by mutations in the Factor VIII (FVIII) gene that encodes for a clotting factor. We are currently researching a therapeutic cell secreted by the circulating FVIII that does not involve treatment with infusion of recombinant FVIII, which involves a high cost. Taking advantage of the HAC vector described above, the FVIII transgene regulation and stability in autologous cell are appropriate in terms of safety, providing a less invasive delivery method for clinical applications.

(2) Elucidating biological processes with chromosome engineering
The development and progression of malignant cells is believed to result from the consecutive accumulation of genetic alterations. This notion is supported by a considerable body of molecular genetic and cytogenetic evidence. This research has suggested that loss of function of genomic imprinting and tumor suppressor genes constitutes one of the most important events in the development of tumors. Our research focuses on the functional analysis of a novel telomerase repressor gene and a long non-coding RNA imprinting gene identified by our group as useful for elucidating the molecular mechanisms of cancer development.

(3) Identification of metastasis-related microRNA and its application to anticancer drugs and diagnostic markers
It has been demonstrated that microRNAs (miRNAs) are aberrantly expressed in cancer, which plays a pivotal role in its development, progression and metastasis. Our research has revealed that down-regulation of miR-143 promotes cellular invasion of 143B cells, a human osteosarcoma cell line. In addition, it was found that intravenous injection of miR-143 with atelocollagen significantly suppressed lung metastasis of osteosarcoma cells in a mouse model. Moreover, we successfully detected lung metastasis-inhibitory miR-143 target genes in the 143B cells. Importantly, the expression level of miR-143 was associated with prognosis in human osteosarcoma patients. Our findings suggest that miR-143 may provide a valuable prognostic marker and may be used in the development of a drug for lung metastasis prevention in human osteosarcoma.