Quick Project Snapshot
Developing SMN gene therapy for SMA and MND
Spinal muscular atrophy (SMA) is the leading genetic cause of infant death with a carrier frequency of 1:50 and incidence of 1:6,000 live births. SMA results from inactivation of the SMN1 gene and retention of the SMN2 gene, leading to ubiquitous SMN protein deficiency and selective spinal motor neuron loss and muscle weakness. SMN is an essential factor for motor neurons regulating alternative splicing and axonal function. SMN gene replacement using viral vectors or antisense oligonucleotides to correct SMN2 splicing show promise in mouse models of SMA. This project involves testing a novel non-viral SMN gene therapy for SMA using "immunogene" technology. Immunogenes consist of motor neuron targeting antibodies complexed with gene expression plasmids. The therapeutic effects of SMN immunogenes will be evaluated on clinical progression, neuropathology and SMN splicing function in mouse models of SMA. Our SMN gene therapy approach will also be applied to mouse models of MND where SMN depletion also occurs in motor neurons.
Therapeutic SMN gene delivery shown by SMN complex accumulation (green) in motor neurons (red) of spinal cord in mice
Turner BJ, Alfazema N, Sheean RK, Sleigh JN, Davies KE, Horne MK, Talbot K (2014) Overexpression of survival motor neuron improves neuromuscular function and motor neuron survival in mutant SOD1 mice. Neurobiol Aging 35:906-915.
Motor Neurone Disease Laboratory
Neurodegenerative diseases have a devastating impact on quality of life and impose a tremendous burden on the health care system. Among neurodegenerative conditions, motor neurodegenerative diseases are the among the most rapidly fatal, with increasing disability and death within 2-3 years from symptom onset. Our laboratory is primarily focused on understanding the molecular basis of motor neuron disease (MND), also called amyotrophic lateral sclerosis (ALS). We are also interested in other motor neurodegenerative disorders, including spinal muscular atrophy (SMA) and spinal bulbar muscular atrophy (SBMA), more commonly known as Kennedy's disease.
Our team employs a combination of cell and molecular biology to unravel MND pathogenesis in patient-derived samples, cell culture and animal models. We seek to identify and understand the primary mechanisms underlying motor neuron vulnerability, stress and injury in MND, while translating our discoveries into relevant biomarkers and targets for effective intervention. Our group is particularly interested in the molecular determinants of protein misfolding and accumulation within neurons, and harnessing endogenous cellular protective mechanisms to combat protein misfolding. We also investigate mechanisms of misfolded protein propagation in the central nervous system in MND with the goal to arrest disease spread.
A further area of investigation is the therapeutic action of survival motor neuron (SMN) protein for SMA and MND. We have discovered that SMN restoration slows disease progression and improves motor neuron survival in mouse models of MND, in addition to SMA mouse models. This has led to development of motor neuron targeted SMN gene therapy approaches for both SMA and MND.
Motor neurons stained for Hb9 (red) Tuj-1 (green)
Prof Dame Kay Davies and Prof Kevin Talbot, University of Oxford
Dr Severine Boillee, Brain and Spine Institute, Paris
Prof Neil Cashman, University of British Columbia
Prof Uri Saragovi, McGill University
Prof Steve Vucic, University of Sydney
Dr Mary-Louise Rogers and Dr Hakan Muyderman, Flinders University
Dr Justin Yerbury, University of Wollongong
Prof Julie Atkin, Macquarie University
Assoc Prof Danny Hatters, University of Melbourne
Prof Philip Beart and Prof Malcolm Horne, University of Melbourne
Australian National Health and Medical Research Council
Bethlehem Griffiths Research Foundation
Cure for MND Foundation
Motor Neuron Disease Research Institute of Australia
Nick Baldi Construction Pty Ltd
SciOpen Research Group
Stafford Fox Medical Research Foundation
All Projects by this LabStimulating autophagy to improve intracellular proteostasis in MNDTargeting exosome-mediated propagation of protein misfolding in MNDDeveloping SMN gene therapy for SMA and MNDGenerating novel mouse models of Kennedy's disease
Dr Lachlan Thompson
Prof David Finkelstein
Scientists in the Neurodegeneration division interrogate how neurones live, die and can be rescued to improve brain function in degenerative conditions such as Parkinson’s and Motor Neuron Diseases. There is no effective treatment for Motor Neurone Disease and the incidence of Parkinson’s Disease is rising alarmingly in our aging community. Gene abnormalities, energy deprivation, toxic rubbish accumulation and inflammation all contribute to a toxic environment for brain cells. Our teams study these events in animal models and cultured cells, with a view to translating knowledge into new therapies for human patients.