Cutting edge

April 21, 2000

A team of scientists in Birmingham is using gene therapy to target cells and treat inherited disorders and killer diseases.

Gene therapy is a new therapeutic approach that offers great promise for several important diseases - including inherited disorders such as cystic fibrosis and muscular dystrophy, and diseases such as cancer and heart disease.

However, realising the potential of the approach is more difficult than originally envisaged, and the success of even sophisticated molecular approaches is limited by inadequate systems for delivery of therapeutic genes.

A particular limitation is that existing vectors are not suitable for targeting following intravenous administration, and hence cannot deliver therapeutic genes to target cells, such as metastatic cancer, that are spread around the body.

Studies at the CRC Institute for Cancer Studies at Birmingham University are focused on resolving this problem, combining biology and polymer chemistry in developing a new generation of vectors for targeted gene delivery. A new technology, based on modification of the surface of gene-therapy vectors using hydrophilic polymers, enables production of vectors with properties tailored for specific biological requirements.

This approach should lead to significant improvements in safety by decreasing unnecessary provocation of the patient's immune system, and by enabling the vectors to gain access to sites of disease.

Linking antibodies to the surface of the polymer-coated vectors allows them to discriminate between diseased and normal cells. This will improve the activity of gene therapy at reduced doses.

A new company, Hybrid Systems Ltd, has been incorporated to manage development of the technology towards clinical application. This development has been assisted by Birmingham Research and Development Ltd, the commercial arm of the University of Birmingham, and the Mercia Fund, established under the University Challenge scheme.

Hybrid Systems's lead technology is based on polymer-coated adenovirus (pc-adeno-virus), where the polymer forms a hydrated shell around the surface of the virus. This is a concept known as steric stabilisation and offers physical protection of the virus from binding antibodies and proteins, while simultaneously preventing the virus from recognising and binding to the receptors it normally uses for pathogenic infection.

It is the inability to regulate interaction of the adenovirus with the patient's cells and immune system that has led to unacceptable side-effects in early US clinical trials using normal adenovirus. An intrinsic property of the polymer allows linkage of targeting agents to discriminate diseased cells from healthy ones.

Targeting will be facilitated by recent developments in identification of vascular addressins; these "natural post-codes" are displayed on the inside of blood capillaries and can be used to identify and target capillaries serving specific organs and tissues. This non-genetic strategy for re-targeting has two main advantages: first, the presence of the polymer coating permits evasion of anti-adenovirus antibodies, which are present in the bloodstream of most gene-therapy patients, and second, the strategy does not compromise safety as the modified properties cannot be passed on to future generations of virus.

The design of pc-adenovirus incorporates requirements stipulated by clinicians who have experience of the limitations with current gene-therapy vectors. The straightforward formulation procedure is compatible with scale-up production, and further benefits of the polymer coat should contribute towards successful clinical development.

Len Seymour is head of the gene delivery group, CRC Institute for Cancer Studies, Birmingham University.

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