Honours Project Book - Faculty of Health Sciences - University of ...

Respiratory and Sleep Medicine
Supervisor/Contact Person
Dr David Parsons
Phone: 8161 7004
david.parsons@adelaide.edu.au
Our group is developing an effective treatment and potentially a life-long correction for the airway disease of Cystic
Fibrosis (CF). This lung disease is the primary cause of worsening health problems in young people with CF, greatly
affecting their quality of life and is the overwhelming cause of early death. We have been supported by grants from
the NH&MRC, the USA CF Foundation, CF Australia and South Australian research funding bodies where we use a
lentivirus-based gene delivery vector to study how to produce safe and effective gene delivery into airway cells.
We use reporter genes such as LacZ and luciferase, to prepare for studies with the therapeutic gene CFTR.
Our work has been focussed across three animal models: mice, sheep and marmosets. Our approach especially
targets airway stem cells in vivo, and in some mouse studies this approach has already produced up to lifetime gene
expression after a single dose event. The field has lacked a simple way to measure the success in airways and lungs,
whether for humans or animal models. To overcome that limitation we have developmed new synchrotron X-ray
imaging techniques with Monash University colleagues. Synchrotron Xrays allow non-invasive viewing of airway
surfaces in live mice, at resolutions close to that of normal light microscopes. We are also now able to examine
mouse lung airflows in 3-D. With further development we expect these techniques will create new options for rapid
and accurate assessment of potential therapies (such as gene-correction) for their effectiveness in improving airway
health in live and intact animal models.
Our research is closely connected with the clinical needs of CF children, and most of our studies are carried out at
the Women’s & Children’s hospital campus in Adelaide. The synchrotron X-ray studies are performed in Japan, and
in 2010 parallel studies began with the assistance of Monash University collaborators at the new Australian
Synchrotron in Melbourne. Finally, we have new state-of-the-art research laboratories in 2012! Through the
enthusiastic initial work of the Cure4CF Foundation Ltd (www.cure4cf.org), and substantial completion funding
provided by the WCH Foundation, the Alan Scott CF research laboratory is now in place in the Gilbert Building at the
WCH
PROJECT (Basic): Airway gene transfer for cystic
fibrosis: converting fluid-based lentiviral gene vector
delivery to aerosol delivery.
.R.
This study is designed to translate our well established
and effective protocols for bolus-delivery of the
lentivirus vector in airway into one that can be
provided in an aerosol form. Aerosols are considered
to be the most practical way to deliver lung gene
therapies in the future.
Preliminary data from our group indicates that the
viability of the vector can be largely preserved with
the incorporation of specific supporting protein
agents in the viral vector carrier fluid. Using a
clinically-applicable electronic aerosolisation device
(Aerogen) the study will be designed to define the
parameters of vector delivery to maintain viability for
in-vitro assessment.
Once those parameters have been defined aerosol
delivery will be tested in the nasal and lung airways
of laboratory mice. The outcome sought in this
Honours year is to define an effective aerosol-based
delivery using in-vitro methods and apply it in-vivo to
laboratory mouse airways.
PROJECT (Basic): Enhancing airway gene transfer for
cystic fibrosis treatment: effects of agents repurposed
from current use in clinical care.
.R.
Agents used clinically to clear CF airways of mucus
and cellular debris may be helpful in improving initial
gene transfer into airway surface epithelial cells, by
enabling better access by the gene vector to the
defective epithelial cells lining the affected airways.
Initial studies will utilise airway-specific cell cultures to
screen a range of these potentially useful
compounds, with lead candidates moving to
preliminary testing using our established gene transfer
methods in the airways of laboratory mice.
The outcome desired is to achieve more efficient
levels of airway gene expression with reporter-genes,
to improve the future opportunities for development
of therapeutically active and effective airway gene
expression using the corrective CFTR gene.
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