Tuesday 30 June 2009
Utrophin injection may offer a new treatment strategy for Duchenne
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene which contains the instructions for making the dystrophin protein- an important component of the structure of muscle. It is thought that another protein called utrophin may be able to compensate for the lack of dystrophin in boys with Duchenne muscular dystrophy since both proteins are structurally similar and appear to have very similar functions.
Professor Dame Kay Davies' laboratory in Oxford is searching for drugs which 'switch on' the utrophin gene to produce more utrophin protein in muscle. One promising candidate drug has been found which is currently being further developed. Meanwhile, new research led by Prof. James Ervasti in Minnesota has shown that an alternative or complementary approach might be to directly inject a modified form of the utrophin protein.
Contents:
What did the research show?
The US researchers produced utrophin protein in the laboratory that was modified by chemically joining it to another protein known as 'TAT' which helps increase the capability of the utrophin to penetrate cells. They tested both the normal full-length utrophin protein and a 'mini-utrophin' which had the non-essential parts of the protein removed so that it was about 40% of the normal length.
The researchers injected the full length and mini-utrophins into the abdomens of mice that are a model of Duchenne muscular dystrophy and looked to see where the proteins ended up. They were able to show that both proteins had effectively penetrated a wide variety of tissues and organs including the heart. They found that the amount of the full length utrophin protein in the muscles was much lower than that of the mini-utrophin. The researchers then injected mice six times over a period of three weeks with the mini-utrophin and found that the mouse muscles were healthier and stronger
What does this mean for patients?
This study has explored an alternative method for treating Duchenne muscular dystrophy by directly injecting utrophin protein. The findings of this research are very promising and may provide a new way to prevent or delay the development of the symptoms of Duchenne muscular dystrophy. This treatment would be applicable to all boys with Duchenne muscular dystrophy, regardless of their type of mutation. It may also be of benefit for Becker muscular dystrophy.
Other strategies under development for muscular dystrophy include gene therapy and the use of stem cells but there are hurdles that need to be overcome before they can be used as a treatment. Firstly, the introduced genes or cells might be recognised as foreign by the body and rejected by the immune system. However, directly injecting modified utrophin protein is unlikely to cause this type of reaction since everybody produces at least a small amount of utrophin (including boys with Duchenne and Becker muscular dystrophy) so the body would be tolerant of it.
Secondly, delivering stem cells or gene therapy to all of the muscles of the body is difficult, but this research shows that when modified mini-utrophin protein was injected into mice it efficiently spread around the body and took up the correct position in muscle cells. So, while the complications of other approaches are being tackled, directly injecting mini-utrophin protein may present a much simpler solution, especially if combined with other approaches to increase the levels of utrophin in the body, such as those being explored by Prof. Dame Kay Davies Laboratory in Oxford.
Studies in animals do not necessarily translate to human beings, so the next step will be to determine if this treatment strategy is successful in larger animal models. The researchers are hopeful that they will be able to start a clinical trial in humans within the next three years. This clinical trial will be necessary to determine if any serious side-effects are caused by the frequent, high doses of the modified utrophin protein that would be given to patients.
Background information
Duchenne muscular dystrophy is caused by mutations in the dystrophin gene. This gene contains the instructions for the dystrophin protein which normally sits in the membrane that surrounds muscle fibres and protects them from damage during muscle contraction. Consequently, in Duchenne muscular dystrophy, the muscle fibre membranes become damaged and eventually the muscle fibres die.
A very similar protein to dystrophin was discovered in 1989 and named utrophin. Because utrophin has a very similar structure and function, it is thought that it might be able to compensate for the loss of dystrophin in Duchenne muscular dystrophy. Low levels of utrophin are present in everyone - including individuals with Duchenne muscular dystrophy - but in insufficient amounts to compensate for the loss of dystrophin. Utrophin is present in larger quantities in the muscles in the fetus (unborn baby) but the gene is mostly 'switched off' when the muscles start produce dystrophin before birth.
Further information and links
More information about Duchenne muscular dystrophy.
More information on the utrophin research in Prof. Dame Kay Davies' laboratory in Oxford.
Read more about the utrophin research we fund.
The original paper is freely available online in the journal PloS Medicine. It is written in scientific language. The reference for the paper is:
Kevin J. Sonnemann, Hanke Heun-Johnson, Amy J. Turner, Kristen A. Baltgalvis, Dawn A. Lowe, and James M. Ervasti. Functional Substitution by TAT-Utrophin in Dystrophin-Deficient Mice. PLoS Med. 2009 May; 6(5): e1000083.
