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
Skeletal disease is a major problem for children with mucopolysaccharidoses (MPS). Patients suffer from early onset osteoporosis and osteoarthritis, severely affecting their quality of life. We will evaluate a lentiviral gene therapy vector developed in-house for its capacity to transduce bone, cartilage, synovial and ligament cells in a mouse model of MPS VI. Our goal is to generate high level, sustained expression of the deficient MPS enzyme and alter the course of skeletal disease in MPS.
Understanding And Improving Treatment Of Premature Infants To Improve Long Term Outcomes
Funder
National Health and Medical Research Council
Funding Amount
$638,517.00
Summary
The last 2 decades heralded many important advances in the care of preterm infants but important gaps in our knowledge remain. Studies undertaken in the preclinical and clinical settings during this Fellowship will enhance understanding of the complex nature of disease in preterm infants. Further, we will develop and evaluate new treatments that enhance growth and development of the premature baby to optimise their long term intellectual, physical, emotional and social outcomes.
Bronchopulmonary Dysplasia – A Regenerative Medicine Approach
Funder
National Health and Medical Research Council
Funding Amount
$480,406.00
Summary
Bronchopulmonary dysplasia is a major leading cause of morbidity and mortality in premature babies. There is no cure. We have previously shown that amnion epithelial cells can reduce the extent of lung damage during early stages of lung development. We aim to understand how amnion cells can promote repair by interacting with existing cell types in order to restore normal lung structure and function. The outcomes from this study will help design clinical trials and develop new therapies.
Amniotic Exosomes - Nanomedicine For Bronchopulmonary Dysplasia
Funder
National Health and Medical Research Council
Funding Amount
$647,058.00
Summary
Extremely premature babies are at serious risk of developing a life threatening chronic lung disease known as bronchopulmonary dysplasia. This is expensive to treat and even babies who survive often end up with lifelong complications. Our team believes that nanoparticles released by placental stem cells have the ability to reverse the disease and that this can be administered without complex medical tools so that parents can administer it themselves after discharge.
Human Amnion Epithelial Cell Therapy For Bronchopulmonary Dyspliasa
Funder
National Health and Medical Research Council
Funding Amount
$1,048,035.00
Summary
Preterm infants, especially those born very early, commonly develop a type of chronic lung disease called bronchopulmonary displasia (BPD). There is currently no cure or means of preventing BPD. Cells from the amniotic membrane that surrounds the developing baby before birth show promise as a treatment, or perhaps even a way of preventing, BPD. This project will use a preterm lamb model of BPD to assess the ability of amnion cells to treat or prevent the disease.
Investigation Of The Influence Preterm Birth On Lung Structure And Function In School Age Children.
Funder
National Health and Medical Research Council
Funding Amount
$204,482.00
Summary
Bronchopulmonary dysplasia (BPD) remains the most significant chronic lung complication of premature birth. While some information on the long term respiratory outcomes in BPD exist there are no comprehensive studies linking lung structure, function and respiratory symptoms and relating these changes to neonatal history. Studies of this kind are essential to ensure future healthcare for these children can be planned accordingly.
The Identification Of Thoracic Targets For Prevention And Intervention In Bronchopulmonary Dysplasia
Funder
National Health and Medical Research Council
Funding Amount
$316,449.00
Summary
The persistence of breathing problems from infancy to later life is a complication of premature birth with lifelong consequences. Breathing problems often occur together with lung disease, but prematurity can also affect heart and blood vessel development, and weakness of the main breathing muscle. We will find out how much the heart, lungs and diaphragm contribute to breathing problems in babies; helping us to better predict, diagnose and treat severe breathing problems in babies born preterm.
Premature babies often need assistance to breathe but this can injure the lung and lead to abnormal lung development and long-term lung disease. We have recently identified 3 factors that we believe are fundamental to initiating this abnormal lung development. We will demonstrate that these 3 factors mediate abnormal lung development following lung injury at birth. This information can then be used to reduce the incidence and severity of chronic lung disease of the newborn.
Lung, Heart And Respiratory Muscle Disease After Preterm Birth
Funder
National Health and Medical Research Council
Funding Amount
$1,328,858.00
Summary
Breathing problems persisting into infancy and later life is an important complication of premature birth with lifelong consequences. Breathing problems often occur together with lung disease, but prematurity can also affect heart and blood vessel development, and weakness of the main breathing muscle (the diaphragm). We will find out how much the heart and diaphragm contribute to breathing problems in babies, and will help us to better predict, diagnose and treat severe breathing problems.