What We Do News An Update from Duchenne Parent Project Onulus Conference in Rome, Feb 2018 Alex Johnson and Megan Mullany from Duchenne UK attended the 16th International Conference on Duchenne and Becker Muscular Dystrophy in Rome which was hosted by Duchenne Parent Project Onlus. The first session covered current pre-clinical and Phase 1 studies for treatments which aim to treat DMD by restoring dystrophin expression such as gene therapy, exon skipping and gene editing. Pfizer and WAVE life sciences updated the community of their gene therapy and exon skipping trials respectively. Pat Furlong from PPMD (US) presented updates on gene therapy in the US and reported that the second patient has now been dosed with AAV microdystrophin gene therapy. Both patients are doing well so far, with no adverse events to report. Professor Thomas Voit from UCL discussed the landscape of gene therapy for DMD and touched on some of the concerns the community may have. Prof Voit highlighted that dystrophin has many isoforms within the body which are used for the development and maintenance of many organs, which means dystrophin is not just required for muscle and heart function. The micro-dystrophin used in gene therapy is a shortened version of the dystrophin gene, this truncation could affect how the protein folds into secondary structures, aswell as maintenance of the protein in the body. Prof Voit then discussed the difficulty of loss of transgene over time. There could be several reasons for this including: dilution of the transgene, muscle remodelling and loss of the transgene through leaky membranes. Due to the loss of transgene in DMD patients, high doses of AAV gene therapy are required to ensure sufficient expression of micro dystrophin occurs. Prof Voit touched on the recently published work of Jim Wilson, which showed liver toxicity in non-human primates when AAV treatments were given at a high dose. Thomas stressed to the community that these studies used a different serotype gene therapy in humans. Additionally, these vectors might not have been produced to the same standards as those in human clinical trials. Although Professor Voit did not seemed worried about the finding of Jim Wilson, he concluded that it is good practice to monitor the patients closely in the first days after dosing. Professor Voit concluded with the following points: 1) Systemic AAV-mediated gene or micro-gene transfer to all body muscles is becoming feasible. 2) Clinical trials phase 1 have started 3) Efficacy will depend on disease state. 4) Vector dilution/loss over time will remain a problem 5) Re-administration to immunized individuals should be feasible but needs more proof of concept work 6) Stem cell failure in DMD remains an unsolved problem. Annemieke Aartsma-Rus presented an overview of CRISPR-Cas9 genome editing for the treatment of DMD. The CRISPR-Cas9 system is made up of two molecules which work together to cut DNA at a specific location. CRISPR-Cas9 could work as a permanent alternative to exon skipping. Although CRISPR-Cas9 has worked effectively in the mouse model for DMD, we are not sure exactly how this will translate into humans. Hurdles for the therapy include ensuring delivery of the treatment to a high enough proportion of muscle fibres as well as the immunity and safety concerns which come with using a viral vector. Annemieke concluded the talk with a realistic viewpoint of the potential of CRISPR-Cas9 technology has for DMD. If this treatment works in patients with DMD it will provide a treatment, not a cure and it will take a while before genome editing trials will start. The next talk focussed on clinical trials in younger patients included updates from Catabasis (Edasolanexent), ReveraGen (Vamorolone) and Mallinckrodt Pharmaceuticals, a company new to the Duchenne community. These companies are trying to develop treatments with less side effects than the current steroids used in clinical practise (deflazacort and prednisolone). The final session of day one focussed on clinical trials taking place in ambulant patients. There were talks from Sarepta on their pipeline of exon skipping drugs, Summit discussed their latest trial results for their utrophin upregulator, Ezutromid, Esparare’s anti-inflamatory and anti-fibrotic drug Rimeporide, Pfizer and Roche also gave talks on their Myostatin inhibitor’s. There was also a session focussing on clinical trials taking place on multiple patient populations at different stages of the disease. Updates came from Sarepta Therapeutics (Exon 51 skipping), Itlafarmaco (Givinostat), Valeria Sansone from Nemo who discussed treatments for non-sense mutations, Santhera Pharmaceuticals (Idebenone) and Capricor Therapeutics (CAP-1002). Please check our website, subscribe to our newsletter and follow us on Facebook and twitter for the latest updates on these clinical trials. You can watch all of the presentations from the conference on YouTube here: Thomas Voit's summary of gene therapy starts at 1hr47min. Annemieke Aartsma-Rus's presentation about genome editing starts at 2hr18min.