Development Of Lentiviral Vectors For The Treatment Of X-linked Severe Combined Immunodeficiency (SCID-X1)
Funder
National Health and Medical Research Council
Funding Amount
$71,434.00
Summary
The first successful gene therapy clinical trial was reported in 2000 with the treatment of X-linked severe combined immunodeficiency (SCID-X1), commonly known as “bubble-boy” disease. The subsequent development of leukaemia in 3 of 11 patients has prompted the need to develop alternative vectors for gene delivery, such as HIV-1-based lentiviral vectors. This project will evaluate the efficacy and safety of lentiviral vectors in vivo, and hence their therapeutic potential for treating SCID-X1.
Induction Of Antigen-specific Humoral Tolerance By RAAV-mediated Delivery Of CTLA4-Ig-antigen Fusion Molecules
Funder
National Health and Medical Research Council
Funding Amount
$524,456.00
Summary
There are many medical situations where immune suppression is required. Available methods lack specificity and risk infection, drug-related side-effects and cancer. We have discovered a novel way of suppressing immunity such that only unwanted responses are eliminated. This involves virus-mediated delivery of antigen fused to CTLA4-Ig. We plan to test this strategy in the context of gene therapy, to work out how it works and to optimise the approach. Success will have broad health implications.
Gene Therapy For The Treatment Of Retinal Dystrophy In The RPE65 Knockout Mouse Using RAAV Virus Mediated Gene Therapy.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
RPE65 is a gene that is found exclusively within the retina. At the moment the exact role of RPE65 is not known, however recent research has shown that mutations in the RPE65 gene have been found in a number of inherited retinal dystrophies (these dystrophies include Leber congenital amaurosis and autosomal recessive retinitis pigmentosa). It therefore appears that a functional, non-mutated RPE65 gene is essential for normal vision. A mouse model of RPE65-related retinal dystrophies has been rec ....RPE65 is a gene that is found exclusively within the retina. At the moment the exact role of RPE65 is not known, however recent research has shown that mutations in the RPE65 gene have been found in a number of inherited retinal dystrophies (these dystrophies include Leber congenital amaurosis and autosomal recessive retinitis pigmentosa). It therefore appears that a functional, non-mutated RPE65 gene is essential for normal vision. A mouse model of RPE65-related retinal dystrophies has been recently developed, by producing a RPE65 knockout mouse breed in which the mouse's RPE65 gene has been mutated into an inactive form. Research on these mice have shown that they develop retinal dystrophies very similar to those seen in patients with mutated RPE65 genes. We propose to use these RPE65 knockout mice to test potential methods for treating the RPE65-related retinal dystrophies in patients. In particular, we will study the potential of using gene therapy to treat these diseases. The project will involve delivering a new, functional RPE65 gene to the retinas of the RPE65 knockout mice. The new, functional RPE65 gene will then replace the inactive, mutated RPE65 gene within the mouse retinas, an action that we predict will be able to stop these mice developing retinal dystrophy. Performing such a study will allow us to improve our understanding of the RPE65-related retinal dystrophies, and provide an indication of whether they can be treated with gene therapy.Read moreRead less
Cell-targeted Gene Delivery Into Human Haematopoietic Stem Cells For The Treatment Of Thalassaemia
Funder
National Health and Medical Research Council
Funding Amount
$171,208.00
Summary
Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various ot ....Thalassaemia is the most common inherited single gene disorder affecting haemoglobin synthesis in red blood cells. It mainly affects people of Mediterranean, Middle Eastern, African, South East Asian, Chinese, and Indian origin. However, large numbers of thalassaemia patients are found nowadays in Australia and other developed countries, due to large population movements in the twentieth century. Approximately 300,000 severely affected children are born each year with thalassaemia and various other abnormalities of haemoglobin synthesis. If untreated, most thalassaemia patients will die within the first few years of life. The vast majority of thalassaemia patients depend on regular blood transfusions every two to three weeks, and on nightly infusions of an iron chelator (a drug for removing excess iron from the blood). These procedures place considerable burden on thalassaemia patients, their families and society, and expose them to blood transmitted infections. The only curative treatment for thalassaemia is bone marrow transplantation from a matching donor. However, the vast majority of patients do not have matching donors and thus the only prospect for them to receive such therapy is to replace in their bone marrow cells a copy of the normal set of genes for the synthesis of haemoglobin. The studies in this proposal are therefore designed to test gene therapy protocols on bone marrow stem cells derived from thalassaemia patients. A normal set of globin genes will be delivered to the bone marrow stem cells via non-viral delivery systems and examined for function in an immunodeficient mouse strain that can accept human bone marrow. This research may enable bone marrow transplantation to be applied for the therapy of most patients with thalassaemia, while it may also have a major impact on therapeutic approaches for other haematological anomalies.Read moreRead less
Myelin Repair By Neural Stem Cells Genetically Modified To Secrete Growth Factors TGFbeta Or IGF-1
Funder
National Health and Medical Research Council
Funding Amount
$199,165.00
Summary
The goal is to locally modify the environment in demyelinating lesions to enhance repair and recovery of function. We will use undifferentiated neural stem (progenitor) cells (NSC) as gene delivery vehicles to supply therapeutic growth factors to areas of damage. Implanted NSC integrate readily into the brain, restoring lost functions, without causing damage. They respond to tissue damage by differentiating into appropriate cells to repair defects, features which are particularly valuable where ....The goal is to locally modify the environment in demyelinating lesions to enhance repair and recovery of function. We will use undifferentiated neural stem (progenitor) cells (NSC) as gene delivery vehicles to supply therapeutic growth factors to areas of damage. Implanted NSC integrate readily into the brain, restoring lost functions, without causing damage. They respond to tissue damage by differentiating into appropriate cells to repair defects, features which are particularly valuable where endogenous myelin repair mechanisms have failed. The first approach will determine whether NSC engineered to secrete Insulin Like Growth Factor-1 (IGF1) promote myelin repair. IGF-1 is a potent stimulator of oligodendrocytes, the myelinating cells in the brain. Itstimulates oligodendrocyte proliferation, differentiation and myelin formation so it may reverse the demyelination and oligodendrocyte loss which are hallmarks of disease. The second strategy is to use NSC to deliver TGF-beta directly to demyelinated areas. TGF-beta suppresses autoimmune responses and is central to recovery from episodes of demyelination in multiple sclerosis and mouse models of immune demyelination. Two mouse models of demyelination will be used to determine the effect of implanted genetically modified NSC; inherited Krabbe disease in which a biochemical defect produces progressive toxic damage to myelinating cells, and injection of an antibody to myelin oligodendrocyte glycoprotein, which induces immune-mediated myelin damage. The behaviour and survival of IGF-1 or TGF-beta secreting NSC, the impact on the quantity of myelin, number of oligodendrocytes and nature of the cellular response to therapy will be quantified. The need for effective therapy of demyelination is urgent. Successful delivery of growth factors to support myelin repair combined with oligodendrocyte replacement would be a significant advance towards treatment for MS, Krabbe disease and other severe neurological disorders.Read moreRead less