liposome technology, nonviral gene and siRNA delivery, protein drug discovery, gene therapy, cancer therapy, and obesity
Research Expertise and Focus
My research over the past 20 years has focused on drug delivery and gene/protein drug discovery. In the field of drug delivery, my lab worked on liposome based nanoparticles and nonviral gene delivery systems. The best-known contribution of my lab in drug delivery is the development of hydrodynamics-based procedure. This procedure has become the most commonly used method for gene function/therapy studies in rodents. We have also developed a computer-controlled injection device for hydrodynamic gene delivery in human-size animals. Combining image-guided catheter insertion techniques, we have demonstrated safe and effective hydrodynamic gene delivery to the liver and skeletal muscle in pigs and dogs. Our more recent work on hydrodynamic gene delivery in baboons, suggests that hydrodynamics-based gene delivery is ready to enter clinic evaluations. In the area of gene therapy, my lab has been working on a treatment of hemophilia in dog models using gene therapy. At the same time, we have made significant efforts in searching for genes that are able to prevent or treat high fat diet-induced obesity and obesity-associated diseases. We have been successful in demonstrating that gene transfer in mice of IL10, IL13, IL6, IL15, SOD3, FGF21, adiponectin or adiponectin receptor gene is effective in preventing high fat diet induced obesity and insulin resistance. The laboratory is now working on gene discovery for treatment of obesity, diabetes, and various cancers. The following are highlights of our research expertise and achievements of the past.
Lipid-based Nanoparticles for Drug Delivery
The early work in my laboratory addressed issues of in vivo delivery using liposomes as a carrier. A major effort was made to study the mechanisms involving removal of liposomes from blood circulation by the RES, especially by liver Kuppfer cells. Efforts were also made to develop cationic lipid-based nanoparticles for gene delivery. We are the first to demonstrate that cationic lipids are highly effective in gene delivery to the lung endothelial cells by intravenous injection in mice. We identified factors that are critical for mouse gene delivery activity including the lipid to DNA ratio, cationic lipid structure, and the helper lipids included in the formulation. More importantly, we found that gene transfer activity of cationic lipid-based carriers is determined by the retention time of DNA in the lung, not the complex structure formed between cationic lipids and DNA. Our work is considered a major milestone in nonviral gene therapy and has served as the basis for development of new nonviral vectors in the past 15 plus years. The representative publications of our earlier work are as follows:
- Dexi Liu, Qingru Hu and Young K. Song (1995) Liposome clearance from blood: different animal species have different mechanisms. Biochim Biophys Acta 1240:277-284.
- Feng Liu and Dexi Liu (1996) Serum independent liposome uptake by mouse liver. Biochim Biophys Acta. 1278:5-11.
- Qingru Hu and Dexi Liu (1996) Co-existence of serum dependent and independent mechanisms for liposome clearance and involvement of non-Kupffer cells in liposome uptake by mouse liver. Biochim Biophys Acta 1284:153-161.
- Dexi Liu (1997) Biological factors involved in blood clearance of liposomes by liver. Adv Drug Del Rev 24:201-213.
- Feng Liu, Hongwei Qi, Leaf Huang and Dexi Liu (1997) Factors controlling the efficiency of cationic lipid-mediated transfection in vivo via intravenous administration. Gene Ther 4:517-523.
- Young K. Song, Feng Liu, Shao Yuo Chu and Dexi Liu (1997) Characterization of cationic liposome-mediated gene transfer in vivo by intravenous administration. Hum Gene Ther 8:1585-1594.
- Young K. Song, Feng Liu and Dexi Liu (1998) Enhanced gene expression in mouse lung by prolonging the retention time of intravenously injected plasmid DNA. Gene Ther 5:1531-1537.
- Tan Ren, Young K. Song, Guisheng Zhang and Dexi Liu (2000) Structural basis of DOTMA for its high transfection activity in mice. Gene Ther 7:764-768.
- Keunsik Kim, Yixiong Lei, Donna B. Stolz and Dexi Liu (2007) Bi-functional compounds for targeted hepatic gene delivery. Gene Ther 14:704-708.
- Mark Kay, Dexi Liu and Peter M. Hoogerbrugge (1997) Gene therapy. Proc Natl Acad Sci USA 94:12744-12746.
- Dexi Liu, Tan Ren and Xiang Gao (2003) Cationic transfection lipids. Cur Med Chem 10:1005-1013.
Hydrodynamic Gene Delivery
The above contribution to nonviral gene delivery has led to a new research direction in my laboratory that focuses on a physical approach for gene delivery. Our effort has led to the development of a new method called hydrodynamic gene delivery. This delivery system has become the most popular method used in the field of gene therapy. Together with others, we have contributed to the gene therapy field a totally new tool that allows a rapid assessment of the functions and activity of a given gene or gene sequence in animals. This same method has been employed for the delivery of siRNA and oligos and for genome editing using CRISPR and TALEN technology.
- Feng Liu, Young K. Song and Dexi Liu (1999) Hydrodynamics-based transfection in animals by systemic administration of plasmid DNA. Gene Ther 6:1258-1266.
- Guisheng Zhang, Young K. Song and Dexi Liu (2000) Long-term expression of human alpha1-antitrypsin gene in mouse liver achieved by intravenous administration of plasmid DNA using hydrodynamics-based procedure. Gene Ther 7:1344-1349.
- Guisheng Zhang, Xiang Gao, Young K. Song, Regis Vollmer, Donna B. Stolz, John Z. Gasiorowski, David A. Dean and Dexi Liu (2004) Hydroporation as the mechanism of hydrodynamic delivery. Gene Ther 11:675-682.
- Takeshi Suda, Xiang Gao, Donna Beer Stolz and Dexi Liu (2007) Structural impact of hydrodynamic injection on mouse liver. Gene Ther 14:129-137.
- Takeshi Suda and Dexi Liu (2008) Hydrodynamic gene delivery: its principles and applications. Mol Ther 15:2063-2069.
- Young K. Song, Feng Liu, Guisheng Zhang and Dexi Liu (2002) Hydrodynamics-based transfection: simple and efficient method for introducing and expressing transgenes in animals by intravenous injection of DNA. Meth Enzymol 346:92-105.
- Kenya Kamimura and Dexi Liu (2008) Physical approaches for nucleic acid delivery to liver. AAPS J 10:589-595.
Computer-Controlled Hydrodynamic Gene Delivery for Treatment of Human Diseases
Following the success of establishing an efficient method for gene therapy studies in mice, we moved on to develop a procedure of hydrodynamic gene delivery that is clinically applicable. A computer-assisted injection device, called the Hydrojector, has been developed, and evaluated in large animals including swine, canine, and baboons for its safety and gene delivery efficacy. We are in the position to conduct clinical trials to evaluate the procedure of computer-controlled, image-guided, and target specific hydrodynamic gene delivery. Our system is the first nonviral approach that has been evaluated in non-human primates.
- Takeshi Suda, Kieko Suda and Dexi Liu (2008) Computer-assisted hydrodynamic gene delivery. Mol Ther 16:1098-1104.
- Kenya Kamimura, Takeshi Suda, Wei Xu, Guisheng Zhang and Dexi Liu (2009) Image guided, lobe-specific hydrodynamic gene delivery to swine liver. Mol Ther 17:491-499.
- Kenya Kamimura, Guisheng Zhang and Dexi Liu (2010) Image-guided, intravascular hydrodynamic gene delivery to skeletal muscle in pigs. Mol Ther 18:93-100.
- Kenya Kamimura, Takeshi Suda, Guisheng Zhang, Yutaka Aoyagi and Dexi Liu (2013) Parameters affecting image-guided, hydrodynamic gene delivery to swine liver. Mol Ther – Nucleic Acids, doi:10.1038/mtna.2013.52.
- Kenya Kamimura, Hiroyuki Abe, Takeshi Yokoo, Tsutomu Kanefuji, Yuji Kobayashi, Takeshi Suda, Guisheng Zhang, Yutaka Aoyagi and Dexi Liu (2014) Safety assessment of liver-targeted hydrodynamic gene delivery in dogs. PLoS ONE, doi:10.1371/journal.pone.0107203.
- Tsutomu Kanefuji, Takeshi Yokoo, Takeshi Suda, Hiroyuki Abe, Kenya Kamimura, Yutaka Aoyagi and Dexi Liu (2014) Hemodynamics of hydrodynamic injection, Mol Ther – Meth & Clin Devel, doi:10.1038/mtm.2014.29.
Gene and Protein Drug Discovery for Prevention and Treatment of Obesity
Our more recent work focuses on gene drug discovery using the hydrodynamic-based procedure. Mice carrying a disease such as obesity are hydrodynamically injected with plasmid carrying a gene of interest via the tail vein. The gene product level in mice is checked and the preventive or therapeutic effects against the disease in the animals are assessed by various methods of molecular biology, biochemistry, cell biology, immunology, and histochemistry. With these methods, we demonstrated that high fat diet-induced obesity and insulin resistance can be prevented by over expression of genes that are involved in the regulation of inflammation and energy metabolism. Our work has demonstrated that the traditional method of protein drug discovery involving in vitro expression and characterization can be carried out directly in disease-carrying animals using the procedure of hydrodynamic gene transfer. We believe that our system will revolutionize the way we search for protein drugs.
- Mingming Gao, Chunbo Zhang, Yongjie Ma, Le Bu, Linna Yan and Dexi Liu (2013) Hydrodynamic delivery of mIL10 gene protects mice from high fat diet-induced obesity and glucose intolerance. Mol Ther 21:1852-1861.
- Yongjie Ma and Dexi Liu (2013) Hydrodynamic delivery of adiponectin and adiponectin receptor 2 gene blocks high fat diet-induced obesity and insulin resistance. Gene Ther 20:846-852.
- Ran Cui, Mingming Gao, Shen Qu and Dexi Liu (2014) Overexpression of superoxide dismutase 3 gene blocks high fat diet-induced obesity, fatty liver and insulin resistance. Gene Ther 21:840-848.
- Hao Sun and Dexi Liu (2014) Hydrodynamic delivery of interleukin-15 gene promotes resistance to high fat diet-induced obesity and fatty liver, and improves glucose homeostasis. Gene Ther doi:10.1038/gt.2014.114.
- Parisa Darkhal, Mingming Gao, Yongjie Ma and Dexi Liu (2015) Blocking high fat diet-induced obesity, insulin resistance and fatty liver by overexpression of Il-13 gene in mice, Int J Obesity, doi:10.1038/ijo.2015.52.
- Yongjie Ma, Mingming Gao, Hao Sun, Dexi Liu (2015) Interleukin-6 gene transfer reverses body weight gain and fatty liver in obese mice. BBA-Mol Basis Dis. http://dx.doi.org/10.1016/j.bbadis.2015.01.01
Mechanistic Studies of High Fat Diet Induced Obesity
- Le Bu, Mingming Gao, Shen Qu and Dexi Liu (2013) Intraperitoneal injection of clodronate liposomes eliminates visceral adipose macrophages and blocks high-fat diet-induced weight gain and development of insulin resistance. AAPS J15:1001-1011.
- Mingming Gao, Le Bu, Yongjie Ma, and Dexi Liu (2013) Concurrent activation of liver X receptor and peroxisome proliferator-activated receptor alpha exacerbates hepatic steatosis in high fat diet-induced obese mice. PLoS ONE DOI: 10.1371/journal.pone.0065641
- Mingming Gao and Dexi Liu (2013) The liver X receptor agonist T0901317 protects mice from high fat diet induced obesity and insulin resistance. AAPS J15:258-266.
- Yongjie Ma, Yixian Huang, Linna Yan, Mingming Gao and Dexi Liu (2013) Synthetic FXR agonist GW4064 prevents diet-induced hepatic steatosis and insulin resistance. Pharm Res 30:1447-1457.
- Mingming Gao, Yongjie Ma, Chunbo Zhang and Dexi Liu (2015) Cold exposure improves the anti-diabetic effect of T0901317 in streptozotocin-induced diabetic mice. AAPS J DOI: 10.1208/s12248-015-9746-4.
Completed List of Published Work Can Be Found at: Google Scholar