Gene and Stem Cell Therapy

Group Head: Professor John Rasko

The broad aims of the Gene and Stem Cell Therapy Group are to overcome the barriers to successful human gene therapy, develop models to understand the biology of adult stem cells and discover disease mechanisms in diseases such as cancer and genetic disorders. Research is undertaken in five areas: gene therapy; stem cell biology; gene silencing; genetic disorders; and cancer biology. The focus of the work continues to be to improve gene delivery to the precursor cells of all blood cells, known as hemopoietic stem cells (HSCs) and other adult stem cells such as mesenchymal stem cells.

Understanding the mechanisms by which a normal cell becomes cancerous is a daunting task. By studying proteins and RNA molecules that become up or down-regulated in different cancers, we can study the basic biology of cancer and possible future therapeutic opportunities that will arise as the important molecules are dissected. Studying both the transcription factors and microRNAs in these projects will help to define the biochemical pathways and complex inter-molecular machinery involved in neoplasia.

Research focus

Stem cells and gene delivery
One of the major problems limiting stem-cell based therapies is the absence of a clear understanding of the composition of the stem cell pool in humans. The right cell must be targeted for the right application or therapy. HSCs have the capacity to divide to produce countless billions of progeny cells throughout a lifetime and it is these progeny that form the basis of our immune system. We have established the SCID-repopulating cell (SRC) assay using NOD/SCID mice to evaluate different mobilisation regimens and to investigate the long-term repopulating ability of different HSC subsets, including HSCs purified by the Hoescht side population method. We have developed protocols for differentiating non-human primate mesenchymal progenitors into cells of adipogenic, chondrocytic and osteogenic origin. In both HSCs and mesenchymal progenitors we are working to optimise gene transfer using retroviral and adeno-associated vectors. We have achieved the successful introduction of gene modified cells into small animal models to study therapies for diseases of blood and muscle.

Mechanisms of Genetic Disease
For the last decade, the group has collaborated with the group of Victor Lobanenkov at the National Institutes of Health (Washington DC, US), examining the role of the tumour suppressor gene CTCF and its related cancer/testis gene BORIS. BORIS is a putative oncogene, which is normally only expressed in the testis, however it is over-expressed in many different types of tumours. During 2007, we have shown that CTCF and BORIS share a number of protein interactors, whilst also having unique binding proteins that may facilitate their opposing effects as a tumour suppressor gene and an oncogene.

Hartnup disorder is an inborn error of renal and gastrointestinal neutral aminoacid transport. In 2004, we described a breakthrough in this field by cloning and characterising the gene responsible for Hartnup disease, SLC6A19. This work was performed by our laboratory in collaboration with Drs Bröer and Cavanaugh in Canberra and its importance has been recognised by successful peer-reviewed grants from both the National Health and Medical Research Council and the Australian Research Council. During the last three years we have studied the genetic cause of other aminoacid transport diseases including imminoglycinuria, hyperglycinuria and dicarboxylic aminoaciduria.

An understanding of the way blood cell production is regulated in the body has immediate relevance to diseases like leukaemia and the way they are treated. MicroRNAs recently identified as part of endogenous gene silencing control have been shown to be intricately involved in the control of cell development and differentiation. Several years ago, we established an early interest in this area with our report of a highly-specific method to detect microRNAs. We are studying the importance of these regulatory molecules in order to discover their previously hidden functions in normal blood cells and leukaemia in humans. Ultimately this project may lead to novel treatments involving gene therapy and bone marrow transplantation.