Targeted Gene Therapy For Cardiovascular Disease

Lead Research Organisation: University of Glasgow
Department Name: Research and Enterprise

Abstract

This proposal is timely since the recent Department of Health white paper encouraged translational research in gene therapy. This is particularly relevant to this proposal since we are expanding our molecular understanding of disease and engineering novel genetic medicines.
Gene therapy is relatively high profile and public education is very important. In the light of recent events (e.g. SCID) public engagament is critical as we begin to treat patients with genetic medicines. For our proposal this is very important since target patient populations are large and education aimed at understanding gene therapy will be essential. The applicants are very active in this area through our host University and through existing funding councils. In addition, the newly formed British Society for Gene Therapy (www.bsgt.org) has in its consititution the role of BSGT in public education. AHB is a founder member and treasurer of BSGT and hence this will maximise public engagement in the technology and applications of gene therapy. Additionally, during the fundraising campaign for the British Heart Foundation Glasgow Cardiovascular Research Centre (BHF GCRC) AFD has been giving regular talks to lay audiences on genetics and cardiovascular disease.

Technical Summary

Gene therapy remains a realistic treatment option for diverse cardiovascular diseases and provides an invaluable tool for probing molecular mechanisms of disease in pre-clinical models. The mode of gene delivery, the transgene cassette and the longevity of transgene expression in vivo are all critical factors to maximise clinical benefit. Here, we systematically evaluate modified gene delivery vectors based on adenovirus and adeno-associated vector technology and apply this to acute and chronic models of cardiovascular disease. Our programme of work is to rationally construct and characterise a panel of designer gene delivery vectors for cardiovascular gene therapy. We will identify targeting peptides to diseased tissue in a clinically relevant model of cardiovascular disease, the stroke-prone spontaneously hypertensive rat. Subsequently, we will construct a panel of transductionally targeted Ad and AAV vectors incorporating homing peptides in viral capsids that will allow systemic targeting to site(s) of disease. We will focus on first-generation and helper-dependent Ad vectors as well as AAV vectors in order to afford acute and long-term transgene overexpression profiles. Biodistribution profiling will be performed using high throughput Taqman technology. The impact of targeted overexpression of candidate therapeutic genes on phenotypic outcomes in the disease models that include endothelial dysfunction, stroke and myocardial infarction will then be evaluated using a range of techniques including immunohistochemistry, functional studies and MRI. Our programme of work will fully evaluate the unique potential of targeted gene therapy for defined cardiovascular diseases.

Publications

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Kritz AB (2007) Adenovirus 5 fibers mutated at the putative HSPG-binding site show restricted retargeting with targeting peptides in the HI loop. in Molecular therapy : the journal of the American Society of Gene Therapy

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Percie Du Sert N (2017) The IMPROVE Guidelines (Ischaemia Models: Procedural Refinements Of in Vivo Experiments). in Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism

 
Description Lawrence Chan 
Organisation Baylor College of Medicine
Country United States 
Sector Hospitals 
PI Contribution new research tools
Collaborator Contribution paper
Impact JCI paper
Start Year 2006
 
Description gtac 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact open day

interaction with school children
Year(s) Of Engagement Activity 2008