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Keywords | Gene therapy | adenovirus | non-viral vectors | prostate cancer | gene promoters | stealthing | re-targeting |<br />
GIANT<br />
Gene therapy: an integrated approach<br />
for neoplastic treatment<br />
Summary<br />
The translation of genetic knowledge from the human<br />
genome into disease-specifi c therapy for untreatable congenital<br />
disorders and acquired diseases is now becoming<br />
a reality. However, the gene therapy vectors currently used<br />
in experimental settings can be developed for safe clinical<br />
application only if fundamental problems are solved; i.e. the<br />
limitation of vector dose by attachment targeting and<br />
expression control, and a decrease of non-specifi c toxicity.<br />
Minimisation of vector immunogenicity (stealthing) is necessary<br />
to reduce bloodstream and immune-mediated<br />
reduction of eff ective vector concentration.<br />
GIANT will therefore concentrate fi rstly on one uniform<br />
model system and disease target (prostate carcinoma) for<br />
vector testing standardisation and in vitro, preclinical and<br />
clinical vector comparison. We will use a clinically approved<br />
vector backbone of adenoviral constructs re-targeted to<br />
prostate cancer via surface antigens, and hybrid prostatetargeted<br />
promoters. The consortium includes a GMP vector<br />
production facility and clinical facilities with scientifi c and<br />
ethical permission to carry out human cytotoxic gene therapy<br />
trials, guaranteeing effi cient translation of selected<br />
vectors into clinical testing. The biomaterials obtained will<br />
serve to develop new assays for vector distribution, effi cacy<br />
and monitoring of the immune response against various<br />
vector systems.<br />
The GIANT participants have a long record of EU-based scientifi<br />
c collaboration and expertise in ethically approved<br />
clinical vector generation. The SMEs own international patents<br />
on retargeting vectors and target discovery methods,<br />
providing a technology platform for further exploration of<br />
promising targets and innovative approaches to facilitate<br />
treatment of neoplastic diseases.<br />
TREATMENT<br />
Problem<br />
Prostate cancer, particularly in its advanced stages, remains<br />
refractory to conventional therapies and is therefore a good<br />
target for gene-based therapies. However, without adequate<br />
specifi city and a fundamental knowledge of the parameters<br />
which reduce effi cacy when vectors developed in tissue culture<br />
are employed in human subjects, these new gene-based<br />
therapies will fail to become established in clinical practice.<br />
Aim<br />
The aim of the GIANT project is to produce a range of prostate<br />
targeted and stealthed viral and non-viral vectors for<br />
ultimate testing in Phase I clinical studies.<br />
Expected results<br />
• New generations of gene transfer vectors, targeted to<br />
prostate cancer cells.<br />
• Stealthed vectors that have a longer half-life and effi cacy<br />
in human tissues.<br />
• International multi-centre, Phase I clinical trials of gene therapy<br />
for prostate cancer. Acceptance of gene therapy for<br />
prostate cancer in the European Urological Community.<br />
Potential applications<br />
• Gene therapy for prostate cancer.<br />
• Safe, targeted vectors for human gene transfer.<br />
• A greater understanding of the human immune response<br />
against gene transfer vectors.<br />
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