Animal models to study human disease

Lead Research Organisation: Imperial College London
Department Name: Life Sciences

Abstract

The Co-operative Animal models to study human disease is a group of nine research laboratories trying to understand and treat a variety of genetic diseases including cystic fibrosis, asthma, blood and neuroretinal degenerative diseases. Although the diseases are quite different in how they affect patients, they are all caused by underlying mutations in the DNA which can be inherited in families, and they are studied using the same laboratory techniques. The first step in understanding a genetic disease is to genetically map it to a specific part of the total human DNA and to identify the actual gene which ahs the mutations. This has been done for these diseases. The disease can then be studied using cells in culture, which can give a lot of information about what is actually wrong with the cells. However, for many diseases, especially ones affecting very defined tissues of the body such as the retina in eye diseases or epithelia in cystic fibrosis, only a limited amount of information can be gained using cultured cells. Therefore, we will use animal models of these human diseases. The affected animals, usually mice are then used to study the disease, which involved taking tissues from the mice at different stages of development and after treatment with potentially therapeutic drugs. As the basic defect in all these disorders is mutation in the DNA, they can all potentially be treated by gene therapy which is the addition of the correct DNA to the cells of the body, which are affected by the disease. This group of scientists is developing methods for DNA delivery which are suitable for the specific diseases being studied; for instance delivery to the lung for cystic fibrosis and to the neurons for ataxia. The final aim of the research is to develop effective treatments for cystic fibrosis, asthma, some forms of blindness and neurodegenerative diseases. The results of our research and their relevance to the development of novel therapeutic approaches as well as their ethical implications will be widely publicised in meetings and scientific articles

Technical Summary

The aim of the Co-operative is to provide the scientific environment to enable top-notch research using animal models to study human diseases. Mouse models are crucial to study disease processes at the tissue and organ levels, for cell and molecular studies on differentiated cell types for which there are no suitable tissue culture systems and for in vivo assessment of gene therapy approaches. These studies require a large amount of expertise, facilities and equipment, which is beyond the ability of single groups. This co-operative will provide for part of the funding necessary to underpin the common aspects of the research. It will provide the basis for sharing facilities such as dedicated areas and the equipment necessary for production of transgenic mice and rederivation of mouse lines, and gene delivery into animals. Scientifically, the Co-operative will foster the collaborations necessary to provide the width and depth of expertise necessary for internationally-competitive work with animal models of disease and for therapeutic intervention. The groups participating in the co-operative are, all but one, part of Imperial College London and work in, or collaborate with groups who work in, the Sir Alexander Fleming Building at the main South Kensington campus. The Co-operative represents the focus for animal modelling and gene therapy research in this campus.

Publications

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Bolasco G (2011) Loss of Rab27 function results in abnormal lung epithelium structure in mice. in American journal of physiology. Cell physiology

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Buckley SM (2008) Intra-amniotic delivery of CFTR-expressing adenovirus does not reverse cystic fibrosis phenotype in inbred CFTR-knockout mice. in Molecular therapy : the journal of the American Society of Gene Therapy

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Chiang L (2011) Rab27b regulates exocytosis of secretory vesicles in acinar epithelial cells from the lacrimal gland. in American journal of physiology. Cell physiology

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David AL (2006) Ultrasound-guided injection and occlusion of the trachea in fetal sheep. in Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology

 
Description BBSRC Project Grant (Structure/function analysis of Rab- and Myosin-interacting proteins in organelle motility)
Amount £358,564 (GBP)
Funding ID BB/E021689/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 08/2007 
End 07/2010
 
Description FFB funding (Gene therapy in mouse models of choroideremia)
Amount £130,000 (GBP)
Organisation Foundation Fighting Blindness (FFB) 
Sector Charity/Non Profit
Country United States
Start 05/2006 
End 04/2009
 
Description MRC Research Grant (Mechanisms of phagocytosis in the retinal pigment epithelium)
Amount £410,848 (GBP)
Funding ID G0700778 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 12/2007 
End 07/2011
 
Description Wellcome Trust Project Grant (Molecular Pathogenesis of Choroideremia: the role of Rab GTPases in the retinal pigment epithelium)
Amount £271,260 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2006 
End 11/2009
 
Title CHM 
Description New models of Choroideremia, an X-linked retinal degeneration 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2009 
Provided To Others? Yes  
Impact Peer-reviewed publications, insoghts into disease mechanisms and application to begin phase I gene therapy clinical trials 
 
Title SMAR 
Description SMAR-based vectors for non-viral gene therapy 
Type Of Material Technology assay or reagent 
Year Produced 2008 
Provided To Others? Yes  
Impact Persistently expressing vectors that may be useful for non-viral gene therapy 
 
Title CHM 
Description AAV-based gene therapy vector containing the CHM/REP1 gene 
Type Therapeutic Intervention - Cellular and gene therapies
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2012
Development Status Under active development/distribution
Clinical Trial? Yes
Impact Application for phase I clinical trial under review 
URL http://clinicaltrials.gov/ct2/show/NCT01461213?term=NCT01461213&rank=1
 
Description BBC documentary 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact The toxin work contributed to a BBC documentary called "Tetanus kill or cure".

General public awareness.
Year(s) Of Engagement Activity 2007
 
Description Choroideremia patients and families 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Primary Audience Participants in your research and patient groups
Results and Impact The Choroideremia work attracts patients and families to visit the lab on a regular basis to interact with the sicentists and get regular updates on the work being done.

Patients feel a part of the study.
Year(s) Of Engagement Activity 2006
 
Description Press attention 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Primary Audience Media (as a channel to the public)
Results and Impact The gene therapy work received press attention, with articles featured in "The Times" and "Daily telegraph". Additionally, it was featured in the MRC annual review.

Information and awareness of general public.
Year(s) Of Engagement Activity 2007
 
Description School visits 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Primary Audience Schools
Results and Impact The team get invited to secondary schools on a regular basis to speak with 6th formers, their teachers and parents.

Public awareness
Year(s) Of Engagement Activity 2006,2007