The long-term goal of Dr. Ikeda's lab is to develop efficient and safe gene and cell therapy platforms for individualized medicine. Dr. Ikeda's main research interests include induced pluripotent stem (iPS) cell technology as a novel diabetes therapy; adeno-associated virus (AAV) vector-mediated gene therapy for diabetes and cardiovascular disease; and intrinsic immunity against HIV and retroviral infection.
Towards patient-specific iPS cells for a novel cell therapy for type I diabetes
Dr. Ikeda's research interests include:
Gene and cell therapy for diabetes. Induced pluripotent stem (iPS) cell technology enables derivation of pluripotent stem cells from nonembryonic sources. Successful differentiation of autologous iPS cells into islet-like cells could allow in vitro modeling of patient-specific disease pathogenesis and future clinical cell therapy for diabetes. However, an efficient methodology is not available for the generation of glucose-responsive insulin-producing cells from iPS cells in vitro.
Recently, the lab has examined the efficiency of iPS differentiation into glucose-responsive insulin-producing cells using a modified stepwise protocol with indolactam V and GLP-1 and demonstrated successful generation of islet-like cells, which expressed pancreas-specific markers. Importantly, the iPS-derived islet-like cells secreted C peptide in a glucose-dependent manner. The lab is currently working on reprogramming diabetic patient-derived cells into genomic modification-free iPS cells using nonintegrating vectors, as well as studying the therapeutic effects of iPS-derived insulin-producing islet-like cells in a diabetic mouse model.
Additionally, the lab has developed novel pancreatic gene delivery vectors and is currently studying the therapeutic effects of pancreatic overexpression of factors known to accelerate beta cell regeneration and neogenesis in diabetic mouse models.
Gene therapy for hypertensive heart disease. Altered myocardial structure and function secondary to hypertensive heart disease are leading causes of heart failure and death. A frequent clinical phenotype of cardiac disease is diastolic dysfunction associated with high blood pressure, which over time leads to profound cardiac remodeling, fibrosis and progression to congestive heart failure.
B-type natriuretic peptide (BNP) has blood pressure lowering, anti-fibrotic and anti-hypertrophic properties, making it an attractive therapeutic for attenuating the adverse cardiac remodeling associated with hypertension. However, use of natriuretic peptides for chronic therapy has been limited by their extremely short in vivo half-life. Recently, the lab used myocardium-tropic adeno-associated virus serotype 9 (AAV9)-based vectors and demonstrated long-term cardiac BNP expression in spontaneous hypertensive rats. Sustained BNP expression significantly lowered blood pressure for up to nine months and improved the cardiac functions in hypertensive heart disease.
The lab is currently examining the feasibility of this strategy in a large animal model for future clinical applications, as well as further developing a gene therapy strategy for hypertensive heart disease using other therapeutic genes.
Pathogenesis of HIV and retroviruses. Mammalian cells have evolved several strategies to limit viral production. For instance, type 1 interferons stimulate a series of cellular factors that block viral gene expression by degrading viral RNA or inhibiting protein translation.
Previously, Dr. Ikeda's lab unveiled a novel antiviral strategy to limit late stages of viral replication, blocking viral production by tripartite motif 5 alpha (TRIM5alpha) through actively degrading a viral protein. TRIM5alpha is a member of the vast family of TRIM proteins, most of which are poorly characterized. Since many TRIM proteins are upregulated following viral infection or interferon treatment, the lab hypothesized that a subset of TRIM proteins represents a new group of antiviral factors.
The lab is currently studying TRIM proteins' antiviral activities against infection and production of various DNA and RNA viruses. A greater understanding of the roles of TRIM family proteins could lead to a novel molecular strategy for viral infection. In addition to TRIM protein-mediated antiviral activities, the lab is also investigating the biology, epidemiology and pathogenicity of a recently identified retrovirus, xenotropic murine leukemia virus-related virus (XMRV).