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Scientists discover possible new treatment for genetic diseases

March 14, 2003

Scientists from Imperial College London, the University of Leicester, and Hammersmith Hospital have found a way to stop certain types of genetic diseases from occurring by modifying the way DNA is turned into proteins.

The research published in this month's Proceedings of the National Academy of Science shows how the researchers have been able to restore proper expression of defective genes, and that this might potentially have a positive effect in genetic diseases such as spinal muscular atrophy.

The research was carried out at Imperial College London and the University of Leicester as a collaboration between Professor Francesco Muntoni and Professor Ian Eperon.

Professor Muntoni, from Imperial College London and the Hammersmith Hospital comments: "Many genetic diseases are caused by the mutation of just one or two of the 3.2 billion base pairs of DNA which comprise our genome. The technique we have developed with our colleagues at the University of Leicester allows us to correct genetic mutations which result in abnormal splicing, as it is the case for spinal muscular atrophy."

Splicing is part of the process by which genes are converted into proteins. Large chunks of useless and meaningless sequence have accumulated in the genes of higher organisations, and the mutation of just one or two of the 3.2 billion base pairs which make up our genome can interfere with splicing.

To make proteins genes first need to be processed into RNA (ribonucleic acid). The information in the genes is broken up into islands of information called exons, which need to be stitched together, while the meaningless sequences are removed. If the sequence of an exon is changed, splicing can be disrupted, causing genetic mutations.

The researchers were able to stick the right sequences back into the exon by using short pieces of RNA (oligos), which stick to the exon of interest and had been modified to recruit signals that influence splicing. Using this novel strategy the splicing reaction can be manipulated.

This treatment was tested on cells from a patient suffering from spinal muscular atrophy. By putting these oligos into the cells, much of the protein required for the splicing process could be produced, allowing normal development of the cells.

Professor Ian Eperon from the University of Leicester adds: "Although oligos have previously been developed to block expression of genes, this research indicates that we can also use them to restore the proper expression of defective genes. As well as working in diseases with a clear genetic basis such as spinal muscular dystrophy, we are aware that other conditions such as inflammation or cancer involve changes in the splicing of normal genes and our method might allow us to reverse these and facilitate treatment of the illness."

Spinal muscular atrophy is a serious and common disease affecting 1 in 10,000 births, resulting in mortality in babies who have the more serious form. The disease is caused by a mutation in a gene called SMN1. About 1 in 50 people have the defective version of SMN1.

Even though everyone carries a second copy of the SMN1 gene, SMN2, this does not compensate for the problem as a difference in a single base pair from SMN1 in just one exon prevents proper splicing. This novel method, that could have broad applications also in other disease, offers a new strategy to try to correct the defect that causes spinal muscular atrophy.

Leicester, University of