MDF Magazine Newsletter Issue 55 April 2018

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Research Published: 21/02/2018 A recent preclinical study has identified a potential therapeutic target for Charcot Marie Tooth disease (CMT). Although this research is in relatively early stages, it could help to develop a new treatment. Our nerve cells communicate with other cells by sending electrical signals down their long, thin axons. Within the axons are rod-like structures called microtubules, which act a bit like train tracks. They help to transport cargo, such as proteins, mitochondria and vesicles, up and down the nerve cell. This process of axonal transport is disrupted in several neurodegenerative conditions, including some types of CMT. The following four articles are from the website of Muscular Dystrophy UK. Early-stage research identifies potential treatment for CMT The microtubules in the axon can be modified by a number of proteins, which can impact how well they transport their cargoes. One of these proteins, an enzyme called histone deacetylase 6 (HDAC6), has been shown to modify microtubules, leading to impaired axonal transport. Researchers in the lab of Prof Ludo Van Den Bosch, KU Leuven, previously found that inhibiting these negative effects of HDAC6 improved axonal transport in a mouse model of CMT2F. In this new study, they investigated whether this could also be beneficial to a mouse model of CMT2D. The researchers treated the CMT2D mice with an HDAC6 inhibitor called tubastatin A. They found that this stabilised the microtubules and improved axonal transport. This improved nerve By Jenny Sharpe health, resulting in greater muscle function in the mice. Lead author of the study, Dr Veronick Benoy, said in a press release: “These results suggest that disturbed acetylation of α-tubulin may be a common hallmark of different forms of CMT. Moreover, we found a cellular link between HDAC6 and the diseaseassociated protein, indicating that HDAC6 could be linked to CMT disease pathogenesis and that selective inhibition of HDAC6 with a drug could be a beneficial treatment strategy for a wide variety of CMT patients.” This study was published in the scientific journal, Brain. Article online at: http://www.musculardystrophyuk.org/news/news/earlystage-research-identifies-potentialtreatment-for-cmt/ Orphazyme sponsors IBM trial at University College London By Jenny Sharpe Published: 25/01/2018 Danish biotech company, Orphazyme, has assumed sponsorship of a phase 2/3 trial assessing the safety and efficacy of arimoclomal for the treatment of sporadic inclusion body myositis (sIBM). The trial has sites at the University of Kansas Medical Center, USA, and the Institute of Neurology at University College London (UCL). The UCL site is expected to begin recruitment soon; we will let you know when this starts. 24 MDUK’s Chair, Professor Mike Hanna, is the principal investigator at the UCL trial site. He said in a press release: “Arimoclomol has strong potential benefit in patients with this disabling disease. We made the case quite strongly that arimoclomol should be properly tested in a large trial, and it is most exciting that we have now started the next step in the clinical development.” The exact cause of sIBM is not fully understood. Some research suggests that it is partly caused by certain proteins being folded incorrectly. These misfolded proteins accumulate in clumps inside the muscle, causing inflammation and muscle damage. Arimoclomal is an experimental drug that enhances the cells’ ability to re-fold proteins. This could help to clear the toxic clumps in muscles affected by sIBM. You can read more about arimoclomal on Orphazyme’s website. Article online at: http://www.musculardystrophyuk.org/news/news/orphazyme-sponsors-ibm-trial-at-universitycollege-london/
Research Acceleron announce preliminary results from FSHD trial By Jenny Sharpe Published: 31/01/2018 Acceleron Pharmaceuticals has announced preliminary results from its phase 2 trial testing ACE-083 in adults with facioscapulohumeral muscular dystrophy (FSHD). ACE-083 is a drug that inhibits a family of proteins that negatively regulate muscle growth (including myostatin). This approach aims to build muscle mass and improve muscle strength. The trial is split into two parts: • Part 1 is a dose-escalation study. This was designed to identify the highest and safest dose of ACE-083 in adults with FSHD. Participants were divided into three dose groups (150mg, 200mg, 250mg), and received injections of ACE-083 into either the upper leg (tibialis anterior muscle), or the upper arm (biceps brachii muscle). • Part 2 is a randomised, double-blind, placebo-controlled study. This will start once Part 1 is complete. The best dose from Part 1 will be tested in Part 2. Acceleron has released data from the 150mg and 200mg dose groups in Part 1. Overall the drug was well tolerated and no serious adverse events occurred. Magnetic Resonance Imaging (MRI) was used to quantify the volume of the targeted upper leg or upper arm muscle. This was carried out before treatment (the baseline) and three weeks after the last injection of ACE- 083. The results showed that ACE-083 increased the volume of the upper leg by an average of 12.6%, and the upper arm by an average of 13.2%. The amount of fat in the leg and arm muscles also decreased. While these results are promising, they are based on a small number of patients (23 in total) and there was no placebo to compare against. We also don’t yet know what effect ACE-083 has on muscle strength and function. This will be investigated in Part 2 of the study, which is due to start in the second quarter of 2018. Dr Matthew Sherman, Chief Medical Officer of Acceleron, said: “These data support our decision to advance to Part 2 of the Phase 2 trial, which we expect to initiate in the second quarter of this year. We look forward to fully exploring functional outcomes in the larger, placebo-controlled Part 2 of the trial.” Article online at: http://www.musculardystrophyuk.org/news/news/acceleron-announce-preliminary-resultsfrom-fshd-trial/ Genome editing corrects mutation in new Duchenne mouse model By Betty Kao, Royal Holloway University Published: 23/01/2018 US scientists have created a new mouse model of Duchenne muscular dystrophy (DMD) and treated it with an improved genome editing technique. This corrected the dystrophin gene and protected the muscles from damage. While the results of this preclinical study are promising, more research is needed before genome editing can be tested in people with Duchenne muscular dystrophy. The new mouse model has a deletion of exon 50, which is one of the most common mutations causing DMD. This makes it an important tool for future DMD research. Previously, most studies have used the mdx mouse model, which has a different and less common mutation. The exon 50 deletion puts the dystrophin gene “out of frame”. This means that exon 49 can’t join up with exon 51, as the ends of these two exons don’t fit together (see below). This leads to an incomplete, faulty dystrophin protein. To put the gene back ‘in frame’, Professor Eric Olsen and his team at the Wellstone Muscular Dystrophy Research Centre, Texas, designed a CRISPR/Cas9 tool to make a single cut near exon 51. This was packaged into an adeno-associated virus (AAV) and injected into the bloodstream of very young mice with the exon 50 deletion. The CRISPR treatment corrected the dystrophin gene and increased dystrophin production in the heart and muscles of the mice. Different tests showed that the muscles were healthy and muscle strength was improved. This demonstrates that treatment in very early stages of the condition can protect the muscles from damage. When the researchers analysed the dystrophin gene of the CRISPR-treated mice, they found that it had been put in frame by two different mechanisms. One of these involved exon skipping, where exon 51 was ‘skipped’ (you can read more about exon skipping in our factsheet). This resulted in a dystrophin protein missing exons 50 and 51. The other mechanism involved the insertion of a particular DNA letter (called adenosine) next to exon 51. This allowed exon 51 to join up with exon 49, resulting in a dystrophin protein missing only exon 50. No off-target effects were found, which suggests that the Cas9 scissors were cutting the DNA in the right place. However further research is still needed to confirm the long-term safety of CRISPR/Cas9 and how long its therapeutic effect might last. Prof Olson is the founder of Exonics Therapeutics, which aims to develop CRISPR/Cas9 for commercialisation. Article online at: http://www.musculardystrophyuk.org/news/news/genomeediting-corrects-mutation-in-newduchenne-mouse-model/ 25
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