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Hi, everybody. Uh I'm Martina Sandona and I am a postdoc in the University of Rome la Catholic. Uh I'm working and studying Duchenne Muscular Dystrophy and treatments for this pathology since my master degree. So it's a big pleasure for me to do this presentation. And I want to thank the organizers for this opportunity. I will do just a brief introduction on the pathology and on the um FDA approval drugs and then I will follow with the story of HDAC inhibitors. So these are the disclosures and let starts. So Duchenne muscle dystrophy as probably, you know, is a genetic disorder. So it means that it, it is caused by mutations in the dystrophin gene. Dystrophin gene is the largest genes in our body and it produces an important protein needed for the muscles, which is the dystrophin protein. In Duchenne patients, there are mutations that change the, the information inside the gene and cause the complete absence of the protein. So the complete absence of dystrophin inside the muscles. The the mutations uh that cause the, the Duchenne muscular dystrophy are the large deletion, the large duplication and others such as the changes uh in one or more uh nucleotide. The most common mutation uh in Duchenne patients are the large deletions. So the removal of one or more axons from the, from the gene and this cause the an error in inside the information. Uh mm lead by the gene that leads to the absence, the total absence of the protein. So, the total um absence of, of protein inside the muscles. But what is dystrophin protein? Dystrophin is a cytoplasmatic protein that connects the extracellular matrix with the sarcolemma of the muscle fibers. It is part of a complex named dystrophy as dystrophin associated protein complex or da PC complex that link the exocellular matrix to the sarcolemma. So, um this uh binding between the aurar matrix and the sarcolemma through the uh the A PC complex is important for the stability of the muscle and also is important for the transfer of the muscle force. So what happened in Duchenne patient in Duchenne patient? The uh the dystrophin is absent. So it's not produced and there is not the link between the sarcolemma and the extracellular matrix. This absence of the protein increases the myofiber sensitivity to damage after contraction. So it means that every time that muscles are contracted, they are also uh damage and this damage has to be repaired. So, since uh uh dystrophin is lost in all the life of patients, the the this is a chronic situation. So, uh there are several cycles of the generation that is followed by a competitor regeneration. And it means that at late stage of the disease, this chronic situation leads to an expulsion of muscle regeneration potential. So, muscle, the damaged mus muscle could not be repaired but, but they are replaced by fibrotic scars and fat infiltration and they become no more functional. What about the symptoms? Maybe, you know, better than me, but just a brief introduction. Um You do, we know that you have a diagnosis of Duchenne muscular dystrophy is necessary. Uh a genetic uh uh analysis of course, but there are symptoms that could be uh observed also in babies that suggest for this pathology such as the progressive muscle weakness and atrophy, the muscle fatigue, the the frequent falls and the difficulties in jumping, running, and walking at the beginning of the pathology. So at early stage of the disease, the lower extend the muscles are the first that are affected. Indeed by the age of 10 and 12, uh between 10 and 12. Um uh boys, D MD boys lose the ablation and start to use the wheelchair. Then uh D MD boys starts to um lose also the function of the upper external muscles. And since al also heart is a muscle, uh they die due to respiratory uh cardiac dysfunction. Actually, uh there is not a cure for Duchenne muscular dystrophy, but scientists are working hard to develop a complement, complementary therapies that try to um slow down the progression of the disease. The therapies that are studying right now could be divided in two big classes. One of these um is uh uh are the therapies that aim to correct the genetic mutation. So they try to restore the dystrophin uh uh absence. And so they, they restore the dystrophin production. Among these therapies, we can note the gene therapy, the cell therapy and also the genome editing uh like the use of mi mini micro dystrophin. The use of exos skipping strategy and the use of drugs that remove the stop codon on the dystrophin M RN. And also the crypts technology. Uh the the other uh class of therapy therapies that are starting right now are the therapies that aim to um to act on the downstream molecular mechanism of the pathology such as the muscle functionality, the muscle regeneration, inflammation, fibrosis and adipogenesis. Among them, we can note the use of glucocorticoids, the use of utrophin, the use of dil ais inhibitor and the use of drugs that uh modulate the activity of angiotensin. Of course, the um restore the dystrophin production will be the cure because uh they restore the, the um uh the dystrophin inside the muscles. But this type of uh therapies uh present a lot of um adverse events. And also the one of the problem is that the we um the sciences reintroduce the dystrophy in a, in a detrimental environment. So, I strongly believe that the cure for the Duchenne Muscular Dystrophy will be the combination of two in which this kind of uh category will uh um reintroduce um more uh pro regenerative environment in which we can introduce the dystrophin uh in a in, in order to, to have um uh functional effect. So, uh I will start with a brief introduction of the FDA approval drugs and then I will uh um talk about the HDAC inhibitor story. So there are several types of drugs that are um approved by the FDA for the treatment of Duchenne muscular dystrophy. And it it is, they are divided in three classes. One of these is the use of micro or micro dystrophin. The drugs is name is led uh the, the studies, sorry, the study, the, the name of the study is led D and the, the, the goal of this study uh is to use the adenovirus to deliver a gene that leads to the production of the micros. So a shortened my protein or shorten dystrophin. The other kind of drugs um are uh belo belong to the uh category of exos skipping strategy. And they are drugs based on the morpholino antisense oligomers that will um that aim to uh remove one or more axon in order to restore the reading frame of the dystrophin. So, leading to the production of the protein. And the last but not least because in reality, they were the first uh that was uh that were approved by the FDA and the are the glucocorticoids that uh are drugs uh able to reduce the inflammatory, uh state of uh dystrophic muscles. The, the macro dystrophin, uh start the, started the phase one.