The clinical implementation of promising gene therapy strategies requires a broad skill base and appropriate infrastructure, most notably facilities in which clinical grade gene delivery formulations can be produced and used in the context of clinical trials in humans. After much hard work, and with financial support from private donors and the NSW Department of Health, we have completed construction of a state-of-the-art human applications laboratory (HAL) within The Children’s Hospital at Westmead in which patients’ cells can be grown and genetically repaired for use in human clinical trials. We are now uniquely placed in Australia to lead the development and implementation of gene therapy approaches to the treatment of childhood disease.
We were the first group in Australia to treat a genetic disease (SCID-X1, a rare immune deficiency disorder) by gene therapy and only the third in the world. Our efforts in this area are continuing and we are now in the process of extending our translational efforts to the treatment of paediatric brain tumours in collaboration with the Oncology Research Unit in The Children’s Hospital.
Severe Combined Immunodeficiency disorder (SCID-X1)
Methylguanine methyl transferase (MGMT)
X-linked Severe Combined Immunodeficiency disorder (SCID-X1)
In April 2000 a team at Hôpital Necker-Enfants Malades in Paris reported the successful treatment of two infants with the X-linked form of severe combined immunodeficiency (SCID-X1) by gene therapy. This condition and a closely related disorder, Adenosine deaminase (ADA) deficiency, are the first genetic conditions for which gene therapy has achieved clear clinical benefit. SCID-X1 is a rare immune deficiency disorder and is caused by mutations in the common γ chain of several interleukin receptors. Affected infants typically lack both T and natural killer (NK) cells and have functionally deficient B cells. As a result, they encounter life-threatening problems fighting infections and rarely survive past the first two years of life without treatment. This condition has also been termed the “boy-in-the-bubble” disease because in some countries patients are placed in isolation to minimise exposure to infectious agents.
The treatment of choice, with greater than 90% survival, is bone marrow transplantation from an HLA-identical sibling donor. The majority of infants, however, lack such a donor and conventionally undergo an HLA-mismatched transplant with associated mortality rates of up to 30%. In most infants, immunological reconstitution remains incomplete, particularly B-cell function, with resultant life-long requirement for immunoglobulin replacement therapy. Gene therapy offers these infants the prospect of improved survival rates and more complete immunological reconstitution.
In collaboration with the French team, the Gene Therapy Research Unit treated an Australian infant with SCID-X1 by gene therapy in March 2002. A total of 18 children have been treated world-wide and results are very promising in the majority. However, this clinical trial has suffered a major setback with three of these children developing a leukaemia-like illness. A thorough investigation revealed that the leukaemia was caused by the gene transfer vector dysregulating a gene known to be associated with leukaemia. The French team has placed their trial on voluntary hold while the protocol can be redesigned to avoid this risk. This case clearly illustrates that, while gene therapy is becoming a very real prospect, there are many technical hurdles yet to overcome.
We are currently working to develop safer gene transfer vectors for the treatment of SCID-X1 and to establish both laboratory assays and a mouse model that will allow us to evaluate the safety gain achieved. This is one of the most important challenges facing the field of gene therapy today.
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Methylguanine methyl transferase (MGMT)
One of the major stumbling blocks in gene therapy research is our limited ability to deliver therapeutic genes to sufficiently target cells in the body to have a clinical impact. The promising results achieved in the treatment of SCID-X1 have, however, highlighted a critical prerequisite for clinical success despite the limited efficiency of current gene delivery methods. This is the need for genetically repaired cells (bone marrow cells in this instance) to have a selective growth advantage over unrepaired cells. Such an advantage allows the repaired cells to selectively proliferate and reach the numbers required for clinical benefit.
In SCID-X1 and ADA deficiency, this growth advantage is conferred by the nature of the disease. Unfortunately, this is not true for the majority of diseases for which gene therapy is envisaged. Accordingly, in collaboration with the CHW Oncology Research Unit, we are exploring a strategy for conferring a selective growth advantage on gene-modified bone marrow cells using a gene that encodes a DNA repair enzyme called methylguanine methyltransferase (MGMT). Expression of this enzyme in bone marrow cells has the capacity to render them resistant to certain chemotherapeutic agents used in cancer treatment. Our current thinking is that this approach might first be employed to reduce the bone marrow toxicity and associated side effects seen in children receiving chemotherapy for brain tumours. If successful in this context, then this strategy might be adapted for selective expansion of gene-repaired bone marrow cells in a number of other diseases.
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