We believe that it is important to have a a multi faceted approach to our funding, our focus is on the now, on slowing down the march of Duchenne to allow science the time to catch up with the cure. We therefore focus on shorter term projects that have the potential to save this generation of children but with an eye to the future.
Duchenne Muscular Dystrophy is a progressive, life limiting, neuromuscular disease with unmet clinical needs. The absence of dystrophin from the muscle membrane results in membrane fragility during muscle contraction such that the muscle is damaged. Cells of the immune system infiltrate the muscle to clean up the muscle environment and instigate the process of repair. A sequela of this inflammation is the activation of fibro-adipogenic progenitor cells that re-populates the muscle with non-contractile tissue. The suppression of inflammation by steroids is an established 'gold standard' in DMD care; however the side effects of long term use are profound. Preliminary data demonstrated that a novel plant derived compound enhances the oxidative potential of muscle cells following treatment. The potential sequelae of increasing the oxidative status of muscle via this treatment are (i) suppression of the level of inflammation in muscle of DMD patients,(ii) increased resistance to fatigue and (iii) a potential increase in muscle mass.
The therapy, developed at Nationwide Children's Hospital by Dr. Mendell and Dr. Brian Kaspar, is based on adeno-associated virus delivery of follistatin 344 to increase muscle strength and prevent muscle wasting and fibrosis. Because follistatin's mechanism of action is not mutation specific, it could one day treat all people with Duchenne.
According to Mendell, "This is the first gene therapy clinical trial to demonstrate functional improvement in any form of muscular dystrophy, and a major advance for those suffering with muscle disease." Based on that result, Dr Mendell will now test if children with Duchenne Muscular Dystrophy can also benefit from the therapy.
This research aims to find drugs with the potential to increase levels of a protein called utrophin. Utrophin is similar to dystrophin and found in small amounts in adult muscle. Increasing its levels might compensate for the lack of dystrophin seen in boys with Duchenne muscular dystrophy. Professor Dame Kay Davies and her colleagues have already developed one drug, SMT C1100, which is currently in clinical trials. In this project, she aims to identify follow-on compounds that can increase utrophin levels more effectively. This approach is particularly advantageous because it is applicable to all people with Duchenne or Becker muscular dystrophy, whatever their mutation.
Developing a gene therapy for Duchenne muscular dystrophy Professor George Dickson and his team plan to develop a novel gene therapy approach that is aimed at delivering a functional, full-size dystrophin gene to muscle cells using a harmless virus. So far research has been restricted to delivering smaller mini- or micro-dystrophin genes due to restrictions in the size of the DNA fragment that the virus can accommodate. In this project the researchers will use two or three viruses each carrying a different part of the dystrophin gene. In the muscle cell the different parts assemble to form the blueprint to produce a full size dystrophin protein. If successful this approach could be used to treat people with Duchenne as well as people with Becker muscular dystrophy.
This project will investigate new ways of improving the efficiency of stem cell transplantation in degenerating muscle. Professor Jennifer Morgan and her colleagues at University College, London, have already discovered that treating an area of damaged muscle with radiation (like a very powerful x-ray) can increase the ability of transplanted stem cells to repair damaged muscle. As radiation can be harmful this project will investigate other less harmful ways of reproducing this beneficial effect.
Professor George Dickson and his team have developed an innovative technique with the potential to repair the genetic mutation that causes Duchenne muscular dystrophy. The ground-breaking technique, described as genome surgery, could be the first therapy that offers permanent correction of the genetic mutation in a person's own DNA. The technique is relevant to all boys and men with Duchenne muscular dystrophy and could also be used to treat people with Becker muscular dystrophy.
In this project Dr Angela Russell and her PhD student will search for molecules showing therapeutic promise for Duchenne muscular dystrophy. They will use leading edge screening techniques to identify compounds that increase the levels of a protein called utrophin, which can stabilise the degeneration of muscle fibres in the condition. The researchers will investigate how these molecules work inside cells - at a molecular level - and this could identify other therapeutic targets that could also be used to increase levels of utrophin.
Professor Wood's project aims to identify molecules which could be used as biomarkers for Duchenne muscular dystrophy. If successful, these biomarkers could be used to improve diagnosis, measure the progression of the condition more accurately and assess the benefit of drugs in clinical trials without the painful procedure of muscle biopsies. They will also develop improved methods of measuring these molecules which will be better suited for use in clinical laboratories than current methods.
Further reports are also showing great efficacy and results within the dystrophic Zebra fish population being used and Lou has identified further compounds from the Pfizer compound library that have potential and is focusing on 2 molecules now that show the best results thus far.
This is currently in clinical trial with boys being dosed whilst initial results appeared encouraging there was a hold put on the clinical trial due to a dog dying (they use large animals to test the very high doses) The FDA (Fedaral Drug Administration) have subsequently removed the hold and clinical trials have begun again. Further updates will appear as we receive them.
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