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Permalink 04:58:24 pm, by Tom, 746 words, 5275 views   English (UK)
Categories: Information

Progress towards a cure for Duchenne Muscular Dystrophy

Duchenne muscular dystrophy (DMD) is a severe inherited muscular dystrophy that causes progressive muscle degeneration which eventually leads to loss of the ability to use muscles and death, and every year tens thousands of children are born afflicted with the disease. It is caused by mutations in the DMD gene that encodes dystrophin, a protein vital to the maintenance of muscle cell structure and function. Not surprisingly there are several charities around the world dedicated to finding a cure, and it looks as if their persistance will soon pay off.

Earlier this week the NIH announced some exciting results from a study (1) of a cocktail of morpholinos, small artificial molecules also called antisense oligonucleotides which mimic DNA and bind to it, that in a process termed exon skipping act as patches to allow the production of dystrophin where it would otherwise fail due to a mutation in the DMD gene. The team lead by Dr. Eric Hoffman found that they when they injected this morpholino cocktail into the bloodstream of dogs that suffer from duchenne muscular dystrophy skeletal muscle degeneration stopped, though the degeneration of cardiac muscle continued. They chose dogs for this experiment because they accurately mimic the physiological effects of human DMD, so the researchers were able to tell if the exon-skipping approach could actually restore enough of the dystrophin function to halt the progression of the disease. Mouse models of DMD, particularly the Mdx mouse which has a mutation in exon 23 that prevents it from making dystrophin, have proved invaluable to research on exon-skipping and other approaches to treating DMD. Their drawback is that the mice only develop a relatively mild version of the disease, and so are not always ideal if you want the determine whether a "patched" dystrophin will actually prevent muscle deterioration. While the truncated dystrophin protein produced as a result of exon skipping does not function as well as normal dystrophin in this study on dogs, they did demostrate that enough dystrophin function was restored to halt deterioration and make a real difference to patients.

Where this work is an advance on research that we reported on earlier is that it uses an intravenous injection that then relied on the bloodstream to circulate the morpholinos to all muscle groups, rather than directly injecting the morpholinos into each of the muscle that need treatment. This is a significant improvement that will make the technique far more practical in the clinic. The use of a cocktail of morpholinos that each target different mutation sites in the DMD gene is also interesting, many DMD patients have several different mutations in their DMD genes and previous methods using antisense oligonucleotides have only been of potential benefit to a small proportion of patients, whereas the cocktail approach may benefit more that 90% of them.

As I mentioned above a serious drawback with the morpholino cocktail technique was that it failed to restore dystrophin function in the heart, but another recent research paper (2) suggests that this problem can be solved by attaching a cell-penetrating peptide to the morpholino. Using this approach Dr. Qi Lu and colleagues at the McColl-Lockwood Laboratory for Muscular Dystrophy were able to safely restore almost full dystrophin activity in both cardiac and sleletal muscles by intravenous injection of a cell-penetrating peptide linked to a morpholino that patches the exon 23 mutation in the Mdx mouse model of DMD. This is an excellent result, and if it can be combined with a cocktail approach has great potential for the future treatment of DMD.

All in all morpholinos are looking like an increasingly promising approach to treating DMD, and along with other approaches including the drug PTC124 that is currently in clinical trials* and stem cell transplantation, offer hope to the many thousands of DMD sufferers around the world.

*As you might expect the basic research that underpinned the dicsovery of PTC124 and the subsequent pre-clinical evaluation of its efficacy and safety relied heavily on mouse models of Duchenne muscular dystrophy and cystic fibrosis (3).


Paul Browne

1) Yokota T. et al. "Efficacy of systemic morpholino exon-skipping in duchenne dystrophy dogs" Annals of Neurology Published Online: 13 Mar 2009, DOI:10.1002/ana.21627

2) Wu B. et al. "Effective rescue of dystrophin improves cardiac function in dystrophin-deficient mice by a modified morpholino oligomer" PNAS Volume 105(39), pages 14814-14819. DOI:10.1073/pnas.0805676105

3) Hirawat S. "Safety, tolerability, and pharmacokinetics of PTC124, a nonaminoglycoside nonsense mutation suppressor, following single- and multiple-dose administration to healthy male and female adult volunteers." J Clin Pharmacol. Volume 47(4), pages 430-444 (2007) DOI:10.1177/0091270006297140


Permalink 03:42:29 pm, by Tom, 652 words, 3188 views   English (UK)
Categories: Information

Mice show the way to safer stem cells!

You may remember that back in 2007 we reported on a scientific breakthrough that was making the headlines around the world, the development of induced pluripotent stem (iPS) cells, and more recently we have seen how Scotland is becoming a centre for stem cell research. It's therefore not a huge surprise to see Scottish scientists playing a key role in the latest iPS cell breakthrough, one that has once again been reported widely on television and in the newspapers.

iPS cells are adult cells that have been reprogrammed through genetic modification to take on the characteristics of embryonic stem cells, most importantly pluripotency; the ability of a cell to differentiate to become any adult cell type. The hope is that these iPS cells will ultimately be used to repair tissue damaged by accident or disease, and in the shorter term to produce better in vitro cell and tissue models of disease. A drawback with the iPS cells produced to date is that they are made using retrovirus vectors to deliver key genes required for pluripotency to the cells, and afterwards both the viral vectors and pluripotency genes remain integrated into the cell. There are concerns that both the pluripotency genes, especially one named c-Myc that is involved in several cancers, and the viral vectors used might behave unperedictibly with the risk that they might cause cancer in transplant patients. In the work reported in Nature (1) British scientists led by Dr Keisuke Kaji and their Canadian colleagues led by Professor Andras Nagy have got around this problem by using a non-virus vector that contains the pluripotency genes flanked by a sequences that enables them to cut the vector out of the genome, so that once the cells are in a pluripotent state the pluripotency genes can be removed from the genome and the cells differentiated into the required tissue.

For their initial experiments they used mouse fibroblast cells, finding that their method was efficient at turning these cells into iPS cells and that the transforming genes could be removed afterwards. But were these cells really capable of developing into any cell type? Initial in vitro experiments indicated that they could be differentiated into a kind of nerve cell, and when implanted into mice they formed teratocarcinomas, a type of benign tumour containing cells of different tissue types that is a characteristic product of pluripotent cells such as embryonic stem cells. The next test was to see if these virus-free iPS cells could really differentiate and grow into a wide range of normal healthy tissues, and to do this they turned to chimeric mice, where the iPS cells are combined with normal mouse embryonic cells to produce an embryo that contains a mix of both cells. The resulting chimeric mice were healthy, and the iPS cells were found to have contributed to all major tissue types. This is needless to say an experiment that could not be preformed ethically in humans.

Armed with the knowledge gleaned from their mouse work the team applied their technique to the creation of virus-free iPS cells from human fibroblasts, and succeeded in producing iPS cells that expressed the genetic markers seen in human embryonic stem cells. The rest is newspaper headlines!

Amid the hype it is worth remembering that, as scientists are perhaps overly fond of saying, these are still early days and this approach will require much evaluation and refinement in both animals and in vitro before clinical trials can begin, so as Professor Robin Lovell-Badge pointed out it's certainly not the time to stop research on human embryonic stem cells. It is also worth considering that it is knowledge gained from the study of the embryonic stem cells of humans and animals that furnishes us with the knowledge that enables iPS cell production.


Paul Browne

1) Kaji K. et al "Virus-free induction of pluripotency and subsequent excision of reprogramming factors" Nature, advanced online publication 01 March 2009, doi:10.1038/nature07864

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