Chemogenetherapy, the next step in gene therapy
A potential treatment for a group of serious neurological and neuromuscular disorders, which result from the aberrant multiplication of small units of DNA within a gene, is described in the latest issue of the journal Nucleic Acid Research 1.
In this research scientists identify several chemical agents capable of altering the rate of expansion of these unstable DNA sequences. And as disease severity seems to be directly related to the size of the anomalous repetition, chemicals that lead to shortening of the expansion are predicted to help control disease. These results are a crucial, although still preliminary, step into the resolution of a group of potentially fatal diseases for which no cure or effective treatment exists.
Several human neurological and neuromuscular genetic disorders are known to be caused by the expansions of a piece of DNA inside a single gene. While the normal gene has three DNA bases (genes are composed of DNA, which is made up of individual chemicals called nucleotides or bases) in people with this type of genetic disorders the three base unit (or trinucleotide) abnormally repeats itself dozens or even thousands of times. When the abnormal expansion reaches a certain size (which depends on the affected gene) disease emerges. Examples include myotonic dystrophy type one (DM1), the most common variant of muscular dystrophy characterised by generalised progressive muscle wasting, Huntington's disease which results from the specific destruction of the brain cells involved in the voluntary control of movements and inexorably drives patients to death, fragile X syndrome, Friedreich ataxia and several spinocerebellar ataxias.
It has been shown that the size of the inherited trinucleotide repeat correlates with the severity of the disease and the age at onset; those with larger repeat copies tend to have earlier disease onsets and higher disease severity. Additionally, it was also observed that in some cases expansion of the unstable trinucleotides occurs more dramatically in the tissues affected by the disease. This led scientists to propose that expansion occurring at such specific places was directly related to disease and if controlled would affect its outcome. Recent research supports this supposition in DM1 and, more recently, in Huntington's disease.
Mário Gomes-Pereira and Darren G. Monckton at the Institute of Biomedical and Life Sciences working on this premise - that specific tissue expansion of the defected DNA that occurs throughout the body after birth is involved with disease - decided to work in the development of treatments through the control of this dynamic. This type of therapy would have the big advantage of avoid the need of individual treatments to each of the diseases as it acts on a point common to the entire group.
For this Gomes-Pereira and Monckton used a transgenic mouse (that was previously created by Monckton) that carried a segment of human DNA containing the unstable gene responsible for DM1, the expression of which showed tissue specificity as in human patients. The team of scientists treated cells of these mice with several chemicals and observed that a few agents capable of affecting DNA metabolism were also capable of changing the expansion rate of the repeated sequence characteristic of DM1. Caffeine for example, although only in extremely high quantities, was able to increase the rate of expansions. But more importantly, several agents were capable of decreasing the expansion rate, thus opening the door to possible treatment of these diseases.
Gomes-Pereira and Monckton write “Crucially, for the first time, we have identified agents that result in lower rates of expansion, an effect that if reproduced in vivo would be predicted to be therapeutically beneficial.”
Treatment is especially important now when we are starting to realise that gene therapy is much more complicated that initially thought and the possibility of a cure is a long way off even for diseases where the abnormal gene has been identified. Furthermore, this type of treatments has the enormous benefit of treating all the diseases where tissue specific trinucleotide expansion occurring throughout the body after birth is related to disease onset and severity. Although all the illnesses described here result from the anomalous expansion of DNA, they have nevertheless different paths to disease following expansion. Having a treatment that is effective not only at such early stage but also that can be applicable to several diseases would be extremely useful. This is especially true now that the human genome has been sequenced and other illnesses associated with trinucleotide repeats are likely to appear.
Finally Gomes-Pereira and Monckton’s work identifies a series of agents, like caffeine with the capacity to increase the rate of expansions in already unstable genes. Whether this has a pratical application remains to be tested but it is, nevertheless, important information as suggests that disease outcome may result from both genetic and environmental factors. And the more we know, the closer we are to control it.
Chemogenetherapy is a promising new potential treatment and the fact that in 2003 Gomes-Pereira won the “Young geneticist of the year” award while working on this project, together with the fact that a patent of the method is pending shows the potential behind it.
1 Nucleic Acids Research (2004); Vol. 32, pp. 2865-2872
Chemically induced increases and decreases in the rate of expansion of a CAG·CTG triplet repeat
Original paper’s authors
In collaboration with the Observatório da Ciência e do Ensino Superior (OCES)
Financed by the Fundação para a Ciência e Tecnologia (FCT)