Microbubble ultrasound as a tool for gene delivery

Lead Research Organisation: Imperial College London
Department Name: Dept of Medicine

Abstract

Almost all diseases are influenced by genes we inherit from our parents. Some, such as Huntingtons disease, are entirely genetic, whilst many others like cancer, coronary heart disease, or Alzheimer?s disease have a large genetic component. The main premise of gene therapy is that these and many other conditions could be treated by correcting the faulty genes behind many such diseases. Unfortunately, whilst there is a widespread belief that gene therapy will cure many diseases eventually, it has proved very difficult to apply in practice. One of the biggest problems has been in getting the target tissue to take up the genes (which are large molecules and do not enter easily into cells or nuclei) safely without harming or affecting other tissues or causing incidental side effects elsewhere. This project aims to use ultrasound scanning and microbubbles for this purpose. Microbubbles are small gas-filled bubbles that are widely used to improve ultrasound studies in patients. While ultrasound and microbubbles are very safe, the acoustic effects produced by scanning can improve delivery of genes by transiently producing small pores in cell membranes, allowing DNA to enter. This is very exciting, because it would help improve delivery of genes to the appropriate organ using a relatively simple method as most organs can be scanned with ultrasound easily. This project will evaluate and develop this approach in cells and tissues in culture and animal models, so that it may be developed for patient use.

Technical Summary

I have studied novel ultrasound methods, particularly microbubbles (gas filled bubbles around 3 microns in diameter) as tools for imaging over the last 6 years. I now wish to apply the skills and understanding developed to improve delivery and targeting of genetic material. Problems in safe tissue-specific delivery have been one of the main obstacles limiting the safe use of gene therapy. Ultrasound and microbubbles can greatly enhance gene transfer efficiency by a variety of mechanisms, including a direct ultrasound-mediated effects on cell membranes, potentiated by microbubbles, and the use of modified microbubbles with targeting ligands or payloads added. My own pilot data and other recent studies confirms the feasibility of this approach. To this end, I have formed strong collaborative local links in gene therapy, molecular engineering and ultrasound physics, and identified several key industrial collaborators with particular experience in targeting with microbubbles. I will initially focus on improving gene expression in tissues where access to ultrasound and high concentrations of gene vectors and microbubbles are easily achieved, namely vascular and corneal endothelium, liver and muscle. A series of in vitro, ex vivo and in vivo studies will be performed to optimise ultrasound and microbubble parameters. Whilst initially using conventional microbubbles, without ligands or payloads attached, I will also explore the potential of locally-made microbubbles, with targeting or delivery potential, and also of commercially developed agents. Although focussing initially on marker gene expression, early extension to therapeutic gene transfer is envisaged. I intend to apply the methods developed to patient studies later in this project. The technologies developed will also have wide general biomedical application, being applicable to cell transfer of larger molecules and particles in general.
 
Description Wellcome Trust Equipment Grant
Amount £633,226 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2008 
End 03/2012
 
Description Brain analysis - DoC, Imperial 
Organisation Imperial College London
Department Department of Computing
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to data and significant intellectual input
Collaborator Contribution Expertise and compute resources
Impact 19815080 19526505 19272356 19245840 19015039 18982587 18500985 18051100 18051099 18051039 18044611 18044561 17964459 17919930 17888685 17696128 17649910 17633705 17428687 17354950 17354848 17354834 17167996 16860573 20969966 20879376 20382238 20114082 20114079 19815080
 
Description Cognitive Neuroimaging Group 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution significant intellectual input
Collaborator Contribution Intellectual input
Impact 19238472
 
Description Neonatal and fetal imaging 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution software, image acquisition methods, image reconstruction methods, significant intellectual input
Collaborator Contribution Data, clinical information, important intellectual contributions
Impact 19926413 19564309 18952670 18687746 18051100 18044561 17964459 17919930 17888685 17696128 17633705 17354950 17344066 17174575 16882805 16866579 16675269 16452356 19643922 19526505 18383541 18051039 21087938 20980451 20969966 20879376 19926413 19643922 19564309
 
Description Neonatal imaging Group 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution Data acquisition methods, experimental hardware development, image reconstruction, data analysis
Collaborator Contribution Data, significant intellectual content
Impact 19926413 19564309 18952670 18687746 18051100 18044561 17964459 17919930 17888685 17696128 17633705 17606564 17354950 17344066 17174575 17005768 16882805 16866579 16675269 16452356 20971721 20969966 20879376 19926413 19564309
 
Description Optics - Imperial 
Organisation Imperial College London
Department Department of Physics
Country United Kingdom 
Sector Academic/University 
PI Contribution Significant intellectual input
Collaborator Contribution Significant Intellectual Output
Impact 19756100 17632634
Start Year 2007
 
Description Optics - UCL 
Organisation University College London
Department Department of Computer Science
Country United Kingdom 
Sector Academic/University 
PI Contribution significant intellectual input
Collaborator Contribution Significant Intellectual Output
Impact 19756100 17632634
Start Year 2007
 
Description Professor Dominic Wells 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution NA
Impact NA
 
Description Professor Terry Partridge 
Organisation Medical Research Council (MRC)
Department MRC Clinical Sciences Centre (CSC)
Country United Kingdom 
Sector Public 
PI Contribution NA
Impact NA
 
Description Invited speaker for Parent Project Muscular Dystrophy 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Participants in your research and patient groups
Results and Impact Presentations to patient groups by Wells
13th-16th July 2006 Invited speaker Parent Project Muscular Dystrophy Annual meeting, Cincinnati, USA
21st-22nd October 2006. Invited Speaker, Parent Project UK, London
28th April 2007 Invited speaker Duchenne Family Support Group, London
12th-15th July 2007 Invited speaker PPMD, Philadelphia USA
3rd-4th November 2007 Invited Speaker PPUK, London
17th November 2007. Guest speaker at PPUK fundraising dinner in Manchester
18th-19th April 2008, Invited speaker at a symposium of Stiftelsen for Muskeldystrofiforskning, Sweden
6th June 2009 Invited speaker Duchenne Family Support Group, York


NA
Year(s) Of Engagement Activity 2006,2007,2008,2009
 
Description Presentation at Pint of Science 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact I was invited to give a presentation for Pint of Science. I used the opportunity to present the science of using bubbles in medical ultrasound imaging.
Year(s) Of Engagement Activity 2017
URL https://pintofscience.co.uk