EVALUATION OF THE EFFECTIVENESS OF EXPANDED NEWBORN SCREENING BY TANDEM MASS SPECTROMETRY
Funder
National Health and Medical Research Council
Funding Amount
$375,250.00
Summary
Newborn babies in Australia are routinely tested for certain treatable disorders. Testing began in the 1960's with systematic testing for phenylketonuria, a rare amino acid enzyme defect. It causes severe mental retardation which can only be prevented if treatment is begun in the first few weeks of life. By 1997, only three other disorders, congenital hypothyroidism, cystic fibrosis, and galactosaemia, had been added to the testing protocol as tests became available. Using the new technology of ....Newborn babies in Australia are routinely tested for certain treatable disorders. Testing began in the 1960's with systematic testing for phenylketonuria, a rare amino acid enzyme defect. It causes severe mental retardation which can only be prevented if treatment is begun in the first few weeks of life. By 1997, only three other disorders, congenital hypothyroidism, cystic fibrosis, and galactosaemia, had been added to the testing protocol as tests became available. Using the new technology of tandem mass spectrometry (MSMS) it is now possible to screen for up to 30 extremely rare, treatable metabolic disorders simultaneously and cheaply, but it is not clear how effective this is. A formal trial of MSMS screening, randomly assigning babies to be tested or not tested, does not seem feasible because of the rarity of the individual disorders (most with a birth prevalence much less than 1: 50,000). Huge numbers would be needed in the trial for statistical significance. We began MSMS screening in NSW April 1998 and in South Australia in February 1999. Victoria is proposing to start screening now, but there are as yet no plans for this screening in the other states. We would like to assess the effectiveness of MSMS newborn screening using the best possible evidence drawn from all data available in the whole of Australia. We plan to undertake an economic evaluation, comparing costs and benefits such as development, hospitalisations, medical complications and other outcome measures, in screened and unscreened babies and also assess harms from screening. Because only 6 specialised laboratories in Australia, in Brisbane (2), Sydney, Melbourne, Adelaide, and Perth can diagnose these disorders, we are confident that we know of all diagnosed cases of the disorders in question. We hope to be able to show whether or not there is a benefit to affected babies by implementing newborn screening tests for these rare diseases.Read moreRead less
Diseases Of Aminoacid Transport: Genetic, Molecular And Biochemical Studies
Funder
National Health and Medical Research Council
Funding Amount
$394,173.00
Summary
Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hart ....Aminoacids are essential building blocks of all living things. They are taken up and retained in the body by highly specific pumps on the surface of cells. By understanding the mechanisms that control aminoacids, we will not only uncover pathways common to normal biology but also shed light on mechanisms of disease in humans. Specifically, the aminoacidurias include a number of inherited diseases of aminoacid transport that result in failure of uptake and retention of particular aminoacids. Hartnup disease is an inherited disorder of neutral aminoacid transport that can lead to a sun-sensitive skin rash, difficulties in controlling movements and walking and other neurological symptoms including mental retardation. A major feature of Hartnup disease is its clinical variability. We have recently identified the main genetic cause for Hartnup disease, and named the gene SLC6A19. We wish to examine whether the clinical variability observed is a consequence of genetic changes and variability in SLC6A19 and other possible genes. Two other aminoacidurias to be studied are dicarboxylic aminoaciduria and iminoglycinuria; both of which are also variable in their clinical consequences ranging from normality to mental retardation. Owing to the relative rarity of these disorders, we are fortunate to have exclusive access to individuals identified by the largest neonatal screening programme for aminoacidurias in the world, based in Canada, and other clinical cohorts within Australia. We will undertake genetic testing to localise and-or confirm the gene(s) involved in these diseases for the first time anywhere and then seek to explain their clinical variability based on functional analyses. We have established a team of researchers with complementary skills from three sites comprising the Australian Aminoaciduria Consortium. Outcomes from this project should impact on the causes and possible therapies for other important medical diseases including motor neurone disease.Read moreRead less
Role Of The Microtubule Network In Nuclear Transport: Potential Use In Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly imp ....Transport of key proteins that regulate growth and other processes, into and out of the nucleus, the site of gene transcription, is central to the function of eukaryotic cells. Knowledge of the process is largely based on studies using semi-intact cell systems, however, meaning that the role of cytoskeletal elements in nuclear transport has been largely overlooked. Intriguingly, in vivo studies, including our own relating to signalling molecules important in the regulation of cancer, clearly implicate the cellular microtubule (MT) network as playing an integral role in nuclear import. We propose to carry out a detailed examination of the mechanistic basis of the dependence of nuclear import on the MT network of 3 molecules regulating cancer. We will compare the properties of these molecules to those of other nuclear localizing molecules, as well as examine the ability to mediate nuclear import of similar MT-associating sequences from viral and other proteins. The results will establish for the first time, the generality of the dependence of nuclear protein import on cytoskeletal elements. Since the movement of large DNA molecules by simple diffusion is a limiting factor in non-viral gene delivery approaches, the possibility of applying this knowledge to facilitate the transport of DNA encoding therapeutic gene products to the nucleus of target cells, will also be assessed for the first time. We will use the modular sequences that confer interaction with the MT network to assist gene transfer by including them in modular constructs we have designed with this in mind. We will thus be able to test directly for the first time whether MT-interaction can enhance the delivery of DNA to the nucleus and reporter gene expression, with obvious application in gene therapy approaches.Read moreRead less
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.Read moreRead less
Primary Health Care Errors Study: Qualification And Quantification Of Errors Occurring In General Practice
Funder
National Health and Medical Research Council
Funding Amount
$191,000.00
Summary
The General Practice Errors Study (GPES) is a project that aims to examine errors that GPs notice in their daily practice, that affect patient well-being or care. Very little work has been done on this subject in General Practice in any other country, and Australia is the only country with previous research that has attempted to describe GP errors with the Quality in Australia Health Care Study (QAHCS). However, we have so far not had any research that has been done on a representative sample of ....The General Practice Errors Study (GPES) is a project that aims to examine errors that GPs notice in their daily practice, that affect patient well-being or care. Very little work has been done on this subject in General Practice in any other country, and Australia is the only country with previous research that has attempted to describe GP errors with the Quality in Australia Health Care Study (QAHCS). However, we have so far not had any research that has been done on a representative sample of GPs, or been able to quantify the frequency with which different types of errors occur. This study plans to ask a representative sample of GPs in both urban and rural areas to report their errors, so that we can try to quantify the incidence and prevalence of these different error types. No previous work has been done in Primary care which has attempted to determine the rate of recognized errors that occur in the community. In addition, since the last major work on this topic was done between 1993 and 1998, there have been many changes to General Practice, especially in the area of computerisation, and the types of problems that GPs face now may have changed significantly. Anonymous reporting is very important in order to encourage health professionals to admit to their mistakes, and in the past, projects have used paper based reporting forms, making it difficult to offer anonymity and requiring protection for participants under a Commonwealth Act of Parliament. However the GPES project will be the first major study of General Practice errors that uses an on-line anonymous reporting form, and high level encryption, located on a secure web-site, to encourage honest reporting. The reporting form was trialled in the 2001 pilot study. By analysing the types of errors occurring, and their contributing factors, we can target at-risk population groups and develop strategies to improve patient care and prevent future harm.Read moreRead less