Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms c ....Mucopolysaccharidoses (MPS) are a related group of 11 debilitating genetic disorders affecting children. They result from a reduction or total deficiency of an enzyme required for the removal of carbohydrate structures called glycosaminoglycans (gags). Gag degradation occurs inside the cell in specific organelles termed lysosomes and in the absence of the appropriate enzyme, undegraded gag accumulates in the cell. This leads to a range of clinical symptoms and multiple tissue failure. Symptoms common to more than one MPS type include mental deterioration, blindness, abdominal organ enlargement and bone growth problems leading to short stature and bone loss. My laboratory has had a long-term interest in developing treatment for MPS and our research led to the clinical implementation of enzyme replacement therapy (ERT) for MPS VI in 2005. While providing the first effective, multi-tissue treatment for MPS, our research showed that several tissues were not responsive to ERT. These are the brain, cartilage and cornea, thus children on ERT regimens will still suffer from mental retardation, arthritis and blindness. With the goal of treating these particular tissues we have developed a new approach to MPS therapy called substrate deprivation therapy (SDT). Instead of adding back the missing enzyme, SDT acts by decreasing gag production which in turn reduces the level of accumulated gag in cells. SDT results in the correction of MPS cells in culture and reduces several key clinical symptoms in the mouse model of MPS IIIA. In this proposal we will extend our research to evaluate the effect of SDT on brain and bone-joint pathology. Evaluation of efficacy will take place in the MPS VII mouse which exhibits both brain and bone disease and in a new model of MPS IVA developed specifically for this study which exhibits a joint pathology unique amongst the MPS disorders.Read moreRead less
A Study To Determine The Effects Of Heparin/ Low Molecular Weight Heparin In Neonates And Children.
Funder
National Health and Medical Research Council
Funding Amount
$193,000.00
Summary
Blood clots in newborns and children are becoming a more common problem. This is because many children with major illnesses are now surviving due to the remarkable advances in medical and surgical care. Blood clots in children can have devastating long term effects. Little is known about the best way to treat blood clots in children and most treatments are just extrapolated from adult treatment guidelines. This is unlikely to be the best treatment as the type and place of blood clots in children ....Blood clots in newborns and children are becoming a more common problem. This is because many children with major illnesses are now surviving due to the remarkable advances in medical and surgical care. Blood clots in children can have devastating long term effects. Little is known about the best way to treat blood clots in children and most treatments are just extrapolated from adult treatment guidelines. This is unlikely to be the best treatment as the type and place of blood clots in children are very different to adults. In addition, the blood clotting system in children is very different to that in adults. This is especially true for newborns. Over the last four years we have established the largest clinical treatment program for children with blood clots in Australia, and have completed the preliminary work that will enable us to now study a number of aspects of the treatment for blood clots in children. This project will specifically examine heparin and low molecular weight heparin which are the most commonly used antithrombotic (anti blood clot) drugs in children. We will determine the effect of age on the mechanism of action, the optimal drug level for treatment, the frequency of the most common side effect of heparin and do some preliminary work to determine alternative treatment options. Our study will provide the basis for more appropriate use of these drugs in children, which will improve the success of therapy and reduce the risk of complications, ultimately improving the survival and quality of life for sick children affected by blood clots.Read moreRead less
Long-lasting Correction Of The Basic Defect In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$458,500.00
Summary
The airway disease caused by the genetic disease cystic fibrosis (CF) is not yet preventable. Current treatments can only limit the gradually-increasing lung disease and is costly. Our new gene therapy technique introduces a correcting gene into affected airway cells, and it has already worked in the first tests in mice bred with CF. Airways in mice are used to test whether the effect is reliable, effective, and lasts long enough to be useful. The gene is introduced into the airway using special ....The airway disease caused by the genetic disease cystic fibrosis (CF) is not yet preventable. Current treatments can only limit the gradually-increasing lung disease and is costly. Our new gene therapy technique introduces a correcting gene into affected airway cells, and it has already worked in the first tests in mice bred with CF. Airways in mice are used to test whether the effect is reliable, effective, and lasts long enough to be useful. The gene is introduced into the airway using special virus delivery-particles, after conditioning the airway to make it receptive to the particles. The method works in normal mice and in CF mice; it gives long lasting gene transfer from a single dose and seems to affect all airway cell types. The gene transfer may also be occurring in airway stem cells, i.e. the mother cells from which grow all the cells of the airway surface. Until now, no-one else has been able to produce prolonged gene transfer in this way, nor arrange gene transfer into stem cells in live airways. There are now a number of things that we must investigate before we could conduct safety and effectiveness trials in larger animals, or consider moving into clinical trials in humans. We need to understand exactly how our conditioning agent works and is it safe; measure how long the gene correction can last actually in our animals; decide if we can we re-dose animals (if needed) without losing effectiveness because of inflammation or immune responses that might occur; and decide how important the airway stem cells are in producing the length of the gene transfer. Because it has been difficult to measure gene correction in CF airways, we will also test new ways we have developed to measure how well the gene correction works in CF airways. The findings of this project will allow us to develop our method to where we can test it in larger animals, to provide a strong, long-lasting gene correction that will be safe for testing in human clinical trials.Read moreRead less
Therapy For CNS Degeneration In MPS Disorders That Targets Both Glycosaminoglycan And Ganglioside Storage.
Funder
National Health and Medical Research Council
Funding Amount
$368,043.00
Summary
Children with seven of the eleven types of mucopolysaccharidosis (MPS) disorders exhibit a profound, irreversible neurological deterioration that manifests in infancy. This results from the continual buildup of undegraded sugar and fat in brain cells. The goal of this proposal is to prevent the accumulation of lipid alone or both lipid and sugar in the brain in order to alter the progression of neurological disease. Treatment will be assessed in mouse models of MPS.
Distribution Of Monodisperse Aerosols Inhaled By Children For Determination Of Optimal Therapeutic Inhaler Formulations
Funder
National Health and Medical Research Council
Funding Amount
$326,000.00
Summary
Inhalers are the primary form of treatment for asthma, allowing the delivery of lower doses of medication directly to the lungs. Consistent daily use of these inhalers is often necessary to effectively control the symptoms of asthma. Inhalers are now increasingly used to treat infants with lung problems. Many of these inhalers are not designed for use by such young children, who may be unable to perform the breathing techniques necessary for effective use of these inhalers. Not all the drug inha ....Inhalers are the primary form of treatment for asthma, allowing the delivery of lower doses of medication directly to the lungs. Consistent daily use of these inhalers is often necessary to effectively control the symptoms of asthma. Inhalers are now increasingly used to treat infants with lung problems. Many of these inhalers are not designed for use by such young children, who may be unable to perform the breathing techniques necessary for effective use of these inhalers. Not all the drug inhaled by patients will end up in the lungs where it is needed; a large proportion is left in the mouth, throat and stomach. Our earlier studies have shown that there is a large amount of variability in the amount of drug received by children using inhalers. We intend to assess the important factors involved in improving the efficiency of inhaler therapy for children, such as the size of the inhaled particles and the breathing pattern of the child. The results obtained from this study will enable us to determine the best method of delivering these drugs to children so that they only receive the lowest effective dose for treatment of the symptoms of asthma while minimising unwanted effects.Read moreRead less
Estimation Of Transient Increases In Bleeding Risk Associated With Physical Activity In Children With Haemophilia
Funder
National Health and Medical Research Council
Funding Amount
$102,143.00
Summary
Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, ....Haemophilia A and B are genetic conditions which affect 1 in 7,000 males in Australia. These disorders cause frequent bleeding due to problems with the clotting factor in blood. Over the past decade there has been a move to administer clotting factor to children with haemophilia in order to prevent bleeds and the consequent damage to joints that occurs when bleeds occur in a joint. Participation in vigorous physical activity and sport is thought to increase the risk of bleeding. Because of this, children are often given clotting factor prior to playing sport. However clotting factor is extremely expensive. For example, a boy wanting to play tennis three times a week would require three injections of cIotting factor per week at a cost of approximately $250,000 a year. To date there is no good evidence about which physical activities are likely to increase the risk of bleeding. If this information was available clinicians would be able to optimise timing of administration of clotting factor so that it is administered prior to activities associated with high risk of bleeds. Another reason to quantify risk of bleeds associated with activity is to inform decisions about participation in physical activity. Every boy with haemophilia wants to know if he can play sport or ride a skateboard or jump on a trampoline. Informed decisions about participation require accurate estimates of risk. This study will use an innovative design to provide, for the first time, accurate estimates of the risk of bleeding associated with physical activity. This information will form the basis for clinical practice guidelines regarding participation in physical activity.Read moreRead less
ARDAC (Antecedents Of Renal Disease In Aboriginal Children) Follow-up Study
Funder
National Health and Medical Research Council
Funding Amount
$298,268.00
Summary
Indigenous people world-wide have higher rates of kidney failure than non-Indigenous people. Aboriginal Australians have the highest rates of kidney failure in the world, especially in those living in remote areas. The reasons for this are complex, and include well-known environmental risk factors that contribute to many diseases in Aboriginal people - socio-economic disadvantage, higher rates of infection, smoking, alcohol abuse and poor nutrition. There are also biological risk factors more sp ....Indigenous people world-wide have higher rates of kidney failure than non-Indigenous people. Aboriginal Australians have the highest rates of kidney failure in the world, especially in those living in remote areas. The reasons for this are complex, and include well-known environmental risk factors that contribute to many diseases in Aboriginal people - socio-economic disadvantage, higher rates of infection, smoking, alcohol abuse and poor nutrition. There are also biological risk factors more specific to kidney disease such as low birth weight babies, reduced kidney volume, female sex, family history of kidney disease, genetic influences, over and under-nutrition and high blood pressure. Many of these risks may take effect in childhood, resulting in silent kidney damage that may become chronic in adulthood when diabetes and other influences take effect. In order to clarify the degree of risk early influences have on Aboriginal kidney disease before adult confounders complicate the picture, a unique study of early signs of kidney disease in outwardly healthy Aboriginal children was planned. These school children come from different locations across NSW, and have a non-Aboriginal comparator group. The first primary aims are complete: To determine: 1. Rates of blood and protein in the urine, and high blood pressure in Aboriginal as compared to non-Aboriginal children. These are the early markers, or antecedents of kidney disease; 2. If these antecedents differ over urban, coastal, rural and remote regions, and socio-economic areas; 3. Any association between antecedents and other risk factors such as age, gender, birth weight and growth; Secondary aims are currently underway: To determine: 1. The natural history of these antecedents of kidney disease by following these children for a further 4 years; 2. Which risk factors are more likely in children with persisting antecedents -ie the children more likely to develop serious kidney disease.Read moreRead less
Downregulation Of N-myc Oncogene Expression As A Therapeutic Strategy For Childhood Neuroblastoma.
Funder
National Health and Medical Research Council
Funding Amount
$145,990.00
Summary
Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients ....Neuroblastoma is a common cancer of young children which, despite the use of powerful anticancer drugs that cure other childhood cancers, has only a 40% survival rate. Many laboratories have shown that the most aggressive neuroblastoma tumours, which are most resistant to the action of anticancer drugs, have an abnormal number of copies of a cancer-associated gene, called N-myc. Patients whose tumours have multiple N-myc copies have dismal survival prospects, and new treatments for such patients are urgently needed. Several studies, using models of neuroblastoma cells growing in the laboratory, have shown that it is possible to create small fragments of genetic material which can specifically switch off the N-myc gene. When this happens, the neuroblastoma cells behave in a less aggressive and malignant way. We have recently shown that these genetic fragments are capable of reducing the growth of tumours in mice which have been genetically manipulated to develop neuroblastoma. We now want to develop new types of genetic fragments (DNAzymes) that will be even more effective at switching off N-myc and inhibiting neuroblastoma development, because these fragments may be extremely valuable for treating neuroblastoma in patients.Read moreRead less
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the c ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Available evidence suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. The failure to respond well to treatment is assessed by a novel molecular genetic technique developed in our laboratory that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. The major goal of this project is to conduct a clinical trial in which this testing procedure is used at an early stage of treatment, and patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. In addition, the project is also directed towards investigating a range of genes known to have a role in drug detoxification. A number of naturally occurring variations exist for these drug metabolising genes and there is evidence suggesting that specific variations or patterns may influence a cancer's response to treatment. We will therefore examine the genetic patterns present in a large cohort of leukaemias and correlate these patterns with response to treatment. It is anticipated that these studies will help define the most appropriate treatment strategies for children with leukaemia. This project therefore has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less
The Use Of Minimal Residual Disease Detection To Improve Treatment Outcome In Childhood Acute Lymphoblastic Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$374,625.00
Summary
Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of altern ....Leukaemia is the most common childhood cancer, representing approximately 35% of all cases. Despite intensive therapy, the disease frequently recurs in the bone marrow and although children are classified into good and poor prognosis groups at diagnosis based on a number of criteria, relapses nevertheless occur in both groups. Evidence obtained by ourselves and others, suggests that early detection of poor treatment response in the otherwise good prognosis group, and the implementation of alternative therapy when the cancer burden is at a low level, has a high likelihood of improving patient survival. In this regard, we have recently developed a novel molecular genetic technique that can detect and quantitate very low levels of residual leukaemia with great sensitivity and specificity. This technique is ideally suited for use in the routine clinical setting, and as a result of this development, we have now established a clinical trial (ANZCCSG Study VIII) in which patients who have a bad result on this test, will be given more intensive treatment to see if this improves survival rates. A number of research questions will also be addressed in this trial including whether the level of residual leukaemia at the end of therapy is able to predict future relapse that would otherwise not be suspected. It is anticipated that the clinical trial will help define the most appropriate treatment strategies for children with leukaemia. This project, which is at the forefront of such studies worldwide, has major implications for the therapeutic management of children with leukaemia and has the potential of contributing directly to the improved survival of this most common of childhood cancers.Read moreRead less