The Oxford Science Lecture Series

PROFESSOR KAY DAVIES

Professor of Genetics, University of Oxford

"Challenges of Muscular Dystrophy"

24th November 1997

The guest lecturer on November 24 1997 in the 'Oxford Science Lectures' series (run by Oxford AWiSE) was Professor Kay Davies, Head of the Department of Genetics, Oxford University. Professor Davies is researching into human diseases that stem from genetic disorders. From the early days of her career she has focused on the treatment for Duchenne Muscular Dystrophy (DMD), a disease which affects about 1 in 3,000 people, almost exclusively boys, and is usually fatal by the late teens. DMD affects all races. The lecture described the steps being taken by Professor Davies' team towards reducing the symptoms of this distressing and incurable disease through gene therapy.

The dystrophin gene is essential for normal muscle growth and development. If it is defective, the dystrophin protein (which normally attaches itself to the inner face of a muscle cell to provide strength and stability) is shortened or absent. An aberrant dystrophin protein creates holes in muscle cell membranes through which the creatine kinase (CK) enzyme can leak out; CK is elevated in victims and suspected carriers of the disease. The dystrophin genes of a suspected carrier, and of an unborn foetus, can be screened for tell-tale aberrations. 70% of patients with DMD have deletions in the gene which cause the complete absence or only very occasional presence of the dystrophin protein. In the less severe form, Becker Muscular Dystrophy, 70% of the patients have deletions and 90% of the deletions are identical, but BMD patients do produce small amounts of dystrophin, and tend to live longer.

Approaches to treatment of DMD have centred on gene therapy whereby the gene is either replaced or is upregulated with an external agent (eg. a cold virus). In attempting to replace defective genes with intact ones one faces problems of rejection by the host: the intact gene will produce protein products which, although normal, are foreign to the patient, who may then mount an immune response against the treatment and develop a parallel illness. If the immune system is suppressed by drugs the risk of infection increases.

In researching means of preventing rejection of those proteins, Professor Davies' laboratory made the ingenious discovery and characterisation of utrophin, a gene almost the exact size of dystrophin. In post-natal development, utrophin peaks in synthesis and is then downregulated as dystrophin is upregulated. An increase of utrophin leads directly to an increase in dystrophin; thus, gene therapy using utrophin could increase the production of dystrophin in vivo. The breakthrough came when foetal mice lacking both dystrophin and utrophin had the utrophin gene added back and were then born without the symptoms of DMD. In addition, adult mice displaying DMD symptoms had those symptoms reduced when utrophin gene therapy was administered.

Professor Davies' team is now involved in a collaborative study to develop the utrophin gene therapy for eventual use in humans. Work is also in progress to try to find a drug which will allow the production of normal dystrophin in patients with a defective gene. If gene therapy is administered to patients in tandem with a drug preventing toxicity, it could produce the most effective treatment yet for patients. The exciting developments of these trials should be available in the next few years. We applaud the extraordinary achievements of this scientific research, and look forward to its fruition in producing a cure for this otherwise hopeless disease.

For me, it was a special pleasure to dine with Professor Davies afterwards. Her sparkling wit and anecdotes revealed the joy she finds in both her work and her family - an inspiring and outstanding role model for scientists in any field.

Elizabeth Barber

Brasenose College, Oxford