Myotonic dystrophy: A therapeutic approach to target the expanded triplet repeat

Written by the Research Department at the Muscular Dystrophy Campaign.

Myotonic dystrophy (DM1) is caused by an expansion of genetic material within a gene located on chromosome 19. Recent research using human DM1 muscle cells grown in a laboratory has demonstrated the use of specialised techniques to target this faulty sequence and either remove it or block its action. Although not a therapy in its current form, it does offer hope of a treatment for myotonic dystrophy sometime in the future.

Contents:


Background

Myotonic dystrophy (DM1) is the most common adult form of muscular dystrophy and is caused by an expansion of genetic material (called CTG repeats) located on chromosome 19 within the Myotonic Dystrophy Protein Kinase (DMPK) gene. There is no effective treatment or cure for this condition and although the genetic fault is known, the precise mechanism by which this causes the symptoms of myotonic dystrophy is not fully understood.


Potential avenues for treatment

One potential avenue for treatment would be to eliminate the expanded triplet repeats. In a collaborative (Canada, France and the United States) project, researchers have produced a virus (retrovirus) carrying a specific piece of genetic material (antisense RNA) which can target the triplet repeat area in cells and bind to it. This can either cause the destruction of bound genetic material (including repeats) or block its effects.

This research was performed using human DM1 muscle cells, which were grown in the laboratory. In DM1 certain functions of muscle cells are effected, such as the ability to take up glucose and the way the muscle cells transform from immature cells to mature muscle fibres. Reducing the numbers of CTG repeats had a beneficial effect on restoring these functions.


Points to note

(i) In its present form, this research does not represent a therapy. These experiments were performed in human DM1 muscle cells grown up in the laboratory. Techniques applied to cells grown up in the laboratory are often more effective than when performed in a complex organism where many more interactions are taking place between cells and other molecules. This research will now need to be shown to be effective in animal models of the disease before its potential in humans can be fully evaluated.

(ii) Retroviral vectors work by inserting into the chromosomes of the cells they enter. This allows the genetic material within the virus to be copied and passed on to other cells. Two points worth mentioning here is that retroviruses are not efficient at entering mature muscle cells and secondly there is presently some concern as to the site of insertion within the chromosome, which may have harmful effects. The use of alternative vector systems may be explored.

(iii) The constructed piece of genetic code is not only specific to the repeats, it also targets some of the DMPK gene code and the full effect of this within cells needs to be determined.

(iv) The number of repeats within the genetic code of individuals with DM1 differs widely, even within families. This would likely mean that specialised molecules would need to be generated for a range of repeat sizes and then tested for efficacy.

(v) DM2 is also caused by an abnormal repeat sequence (of four letters of genetic code), if this technology is shown to be effective it may have potential for use in DM2.

(vi) Another possible treatment could be the use of ribozymes, which act like biological scissors to cut out unwanted pieces of genetic material. The effectiveness of this technique is also currently being investigated.


What does this mean for me now and in the future?

There is still unfortunately no effective treatment or cure for either form of myotonic dystrophy. Research such as this is encouraging as it moves us closer towards the possibility of a treatment.


Related reading

Journal: Gene Therapy, Volume 10 Number 9. Pages 795 – 803.
Title: Viral vector producing antisense RNA restores myotonic dystrophy myoblast functions.
Authors: D Furling, G Doucet, M-A Langlois, L Timchenko, E Belanger, L Cossette & J Puymirat.

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