The Unfolded Protein Stress Response In Inherited Skeletal Disease: Mechanism And Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$549,092.00
Summary
In genetic diseases, gene mutations commonly cause proteins to fold abnormally. This can cause cell stress resulting in cell death. Our studies will determine the role of cell stress in a clinically important group of skeletal diseases caused by collagen mutations. We will also test how we can use small chemicals to alleviate the damage done to the cells by the misfolded proteins, in the hope that this approach will provide new therapeutic strategies for these disorders.
Mutation Analysis Of Novel Candidate Genes For X-linked Charcot Marie Tooth (CMTX3) Neuropathy.
Funder
National Health and Medical Research Council
Funding Amount
$191,434.00
Summary
Our goal is to explore how peripheral nerves degenerate by identifying the gene mutation causing an X linked form of Charcot Marie Tooth neuropathy (CMTX3). Using bioinformatic resources and state of the art gene mutation scanning we will complete characterisation and systematic screening of candidate genes and novel transcripts in the region. Discovery of this gene will provide a means to determine mechanisms causing axonal degeneration and lead to targeted therapeutic treatment strategies.
The Role Of Huntingtin Misfolding And Oligomerization In Huntingtons Disease
Funder
National Health and Medical Research Council
Funding Amount
$474,329.00
Summary
Mutations in the huntingtin gene cause Huntington's disease by making the gene product aggregate together into non-normal and different sized polymers. However, it is not understood how this process causes cells to die, largely because we don't understand how the abnormal forms accumulate in cells over time. We will examine where in cells the abnormal shapes accumulate and how they cause toxicity. This research will identify critically-needed therapeutic targets against Huntington's disease.
A Saturation Screen For Modifiers Of Epigenetic Reprogramming In The Mouse: Phase II
Funder
National Health and Medical Research Council
Funding Amount
$1,374,820.00
Summary
The building of a complex organism, such as a human embryo, is a self-directed process driven by the genetic information inherited from the parents. As the cells differentiate into a diverse array of tissues, the genetic information does not change. What does change is the epigenetic state of the genome in each cell type. We still understand little about this epigenetic reprogramming except that mistakes in the process lead to death and disease. Our work aims to address this lack of knowledge
Dominant Repeat Expansion Diseases - A Common RNA Mediated Pathogenic Pathway?
Funder
National Health and Medical Research Council
Funding Amount
$281,118.00
Summary
There are fourteen human genetic diseases that are caused by a similar mutation mechanism and have similar clinical outcomes - the loss of function, degeneration and eventual death of nerve cells. This group of diseases includes Huntington's Disease. They are transmitted from parent to offspring such that each child of an affected parent has 50% risk of inheriting the affected gene and therefore developing the disease. The symptoms of these diseases typically develop later in life - between the ....There are fourteen human genetic diseases that are caused by a similar mutation mechanism and have similar clinical outcomes - the loss of function, degeneration and eventual death of nerve cells. This group of diseases includes Huntington's Disease. They are transmitted from parent to offspring such that each child of an affected parent has 50% risk of inheriting the affected gene and therefore developing the disease. The symptoms of these diseases typically develop later in life - between the ages of 35 and 50 years. While the different genes for these diseases have been identified the pathways that lead from their similar form of mutation to their similar clinical outcomes are not yet understood. Some evidence suggests that certain of these diseases have a common toxic component but this component is not shared by all of the disease genes and so an additional agent that they have in common is being sought. This research will use a genetic model organism - the vinegar fly, Drosophila melanogaster, to test the identity of a good candidate (RNA) for a common toxic agent and to provide information about the pathway by which RNA leads to nerve cell degeneration and death. Accurate and complete knowledge of the identity and composition of the pathways that lead from the mutation to the disease are crucial for correct target identification in the development of drug leads.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.
Improving The Safety Characteristics Of Lentiviral Vectors.
Funder
National Health and Medical Research Council
Funding Amount
$296,250.00
Summary
Gene therapy holds great promise for the treatment of many types of disease including inherited disorders, cancer and cardiovascular disorders. However, the potential of gene therapy has in many cases been limited by the lack of suitable technologies for gene delivery. We have developed a novel gene delivery vehicle from human immunodeficiency virus type 1 (HIV-1). Although this vehicle has many of the characteristics desired of a gene therapy vector its derivation from a retrovirus, particularl ....Gene therapy holds great promise for the treatment of many types of disease including inherited disorders, cancer and cardiovascular disorders. However, the potential of gene therapy has in many cases been limited by the lack of suitable technologies for gene delivery. We have developed a novel gene delivery vehicle from human immunodeficiency virus type 1 (HIV-1). Although this vehicle has many of the characteristics desired of a gene therapy vector its derivation from a retrovirus, particularly one with such an unenviable reputation, raises obvious safety concerns. In order to properly address this issue it is necessary that the vector is carefully designed and properly tested. This project aims to continue our rational, systematic and stepwise approach to the development of our vector with the aim of producing a vector that can be used with a high degree of confidence in its safety, such that it is suitable for clinical usage. Given the highly desirable properties of these vectors, and the wide range of diseases where their use is being considered, the availability of such a vector will have great significance for the widespread practical application of gene therapy. Indeed, several of the projects we are developing with our vector will in all likelihood lead to lead to clinical trials and it is clear that the conduct of these trials will depend on the availability of a suitable vector.Read moreRead less