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Genomic information allows the development of therapies targeted at specific genetic errors

Suppose scientists could discover how changes to our genome alter the products which genes make – and then determine how these changes result in diseases such as cancer. With modern technology, it might then be possible to make medicines to overcome the effects of these changes because they directly target the cause.

This goal may seem like the remit of science fiction, but for some diseases it has become a reality: treatment targeted directly at the genetic cause.

Researchers have been able to design molecules in the laboratory which may stop or alter the effects of the genetic changes. This has been possible by understanding what these genetic changes do – for instance, resulting in the production in the body of a completely new protein (as in chronic myelogenous leukaemia) or changing the shape of an enzyme (as in melanoma).

The first truly effective targeted agent to be developed was imatinib (Gleevec) which is used in the treatment of Philadelphia-chromosome-positive chronic myelogenous leukaemia (CML). In CML, a new protein is made as a result of genomic changes; imatinib targets this molecule directly.

Another example was a treatment for melanoma which was developed by understanding the effects of a mutation causing the disease

Research found that one particular mutation in one copy of a gene (called the BRAF gene) is found in about 90% of patients with melanoma. This change causes the gene, which produces an enzyme, to be constantly active, and not able to respond to signals to control it. Scientifically, this alteration to the DNA sequence caused one amino acid in the enzyme protein to be changed for another: this would be predicted to change the shape of the protein. Researchers reasoned that if melanoma was caused by the enzyme being constantly active because its shape had been changed, it might be possible to design a compound which would interact with the enzyme molecule which would inhibit its activity. This is exactly what was achieved: with the result of a therapy called PLX4032. To make sure the compound was safe and effective, a clinical trial was held with dramatic improvements compared with existing therapies.

These are examples of conditions where molecules have been designed to target specific genetic alterations or their effects. For some diseases, however, antibodies which are targeted at particular molecules have been developed. For instance, in neurofibromatosis type 2 (NF2), usually benign tumours form from the tissue that covers nerves. Nerves can be compressed by the tumour – this is a particular problem when tumours develop on the auditory nerves, resulting in a person losing their hearing. In some patients, an antibody (bevacizumab; Avastin) against a vascular growth factor can reduce the size of the tumours. Professor Gareth Evans describes the results of using this monoclonal antibody in a clinical trial with patients with NF2.

Treating Schwannoma tumours in NF2 patients with Bevacizumab

The pace of development of such effective medicines is quickening remarkably, with at least seven licensed by the FDA in the United States in 2011 alone. Targeted drugs approved by the US Food and Drug Administration in 2011

In specialist clinics, gene-therapy of severe combined immuno-deficiency disease (SCID or Bubble-baby) has already been successfully tried in a few patients with decade-long protection.