MyFSHD

"Failure is not an option". Seth, Sarah and Eva provide their experiences and perspectives on growing up with early-onset FSHD and why (and how) they should be included in the therapeutic development and testing process.

"Houston, we have a problem". While it is exciting for the FSHD community that clinical trials are here and more are coming soon, the system is not working for everyone. Our young and non-ambulatory FSHDers of all ages are currently being left behind. Today, Maggie and Kate from the Cure FSHD for All initiative ask for inclusion into clinical trials; it is good business, good science, and the right thing to do. And if that is not feasible, then please consider expanded access to experimental therapeutics for those most in need and with no other options.

"You're gonna need a bigger boat!" Today we discuss the third compound going to clinic emerging from Neil Camarta's "Shark Tank" meetings. This one from Satellos was designed to address the regeneration deficit in DMD caused by reduced asymmetric muscle stem cell division, and is now being repurposed for FSHD to potentially boost muscle regeneration regardless of DUX4 status.

"If you want something bad, you have to fight for it. Step up you game, Scott. Break out the L-word". Today we discuss a little more on the Epicrispr clinical trial and preview the upcoming Scholar Rock, Soufflé and Dyne phase I/II clinical trials. As you know, the Devil is in the details. We are tingling with anticipation for the upcoming clinical trial report from Epicrispr to be presented at the World Muscle Society first week of October (DNA methylation and DUX4 target gene expression data from biopsies, please). We are still very hopeful for the Avidity Phase 3 trial currently in 45 sites around the world! Sure the DM1 trial tanked, but their DMD trial is progressing well. Regardless, new therapeutic approaches are here. We are very high on Soufflé's cell specific targeting platform as well as Dyne's alternate transferrin receptor targeting, both of which we hope will allow for increased dosing, more DUX4 knockdown, and greater intervals between dosing. We are also cautiously optimistic about Scholar Rock entering the FSHD space coming off of their recent FDA approval for a combined therapy in SMA. Truly exciting times (and more to come!), and we will try to keep you all updated on the science.

"What is magic? Magic is deception, but deception designed to delight, to entertain, to inspire. It is about belief. Faith." Today we discuss the recent exciting data presented by Epicrispr and their EPI-321 gene therapy at the IRC , and more importantly, we discuss what they (shockingly) did not say, present, or disclose. Hmmmm..... While it is inconceivable (to us) that a company would not test if their specific treatment was actually working, it is equally unconscionable that a company (with the help of their foundation partners) would knowingly mislead the community, so we know that is not happening, but we do have some questions and look forward to clarification and real validation in the future.

"It's not who I am underneath, but what I do that defines me." We celebrate World FSHD Day with those that are making a difference in the world (and our fathers -- Happy Father's Day!) and then discuss what we would like to hear from the FSHD clinical trial companies at the upcoming FSHD International Research Congress.

"I think the question we should be asking is, do you believe in this thing or not?" We discuss the value of MRI-informed muscle biopsies compared with uninformed biopsies, how we go about interpreting FSHD clinical trial gene expression data, and after the song, we show the Jones Lab CRISPRi presentation from the ASGCT annual meeting in Boston.

"I'm not bad. I'm just drawn that way." Today we finish up some questions on clinical trials, therapeutics, what may be in the future, and other random FSHD topics. Good times :)

"Blue Horseshoe loves Anacott Steel." Today we cover recent clinical trial news in the FSHD space and delve a bit deeper into some topics from part 1 of our Reddit Q&A. **Updated version** The lowlight was Roche canceling their trial. The highlight was Sarepta's announcement of preliminary clinical data. Getting siRNAs, ASOs, and viruses into liver is easy because liver is filled with leaky capillaries, however, muscle is poorly vascularized and blood vessels have tight junctions so targeting cell receptors for enhanced transcytosis greatly enhances skeletal muscle delivery. Sarepta's targeting of the alpha v beta 6 integrin is a great advance in delivery of siRNA against DUX4 and, as predicted, shows the best DUX4 knockdown we have seen so far.

"I am the eyes and ears of this institution, my friends." You asked, we (try to) answer your questions. Part 1 of 2. There is no song in this version due to copyright issues causing it to be removed for some of our international listeners, otherwise, same as the original version.

"So, Mr Tipton, how could it take you five minutes to cook your grits when it takes the entire grit-eating world twenty minutes?" We discuss the initial Epicrispr Biotech press release pertaining to their EPI-321 phase 1/2 clinical trial and the big picture science behind the RESTEM phase 1/2 clinical trial in progress and the Scholar Rock upcoming phase 2 clinical trial.

"That's super frustrating. It just makes me wanna pick up whoever is standing closest to me and throw them through this window and out into the infinite abyss of nothingness!" Brad, our angry Dad, is back with some questions about clinical trials and muscle building.

"There's another old saying, Senator: Don't piss down my back and tell me it's raining." We know a lot of you don't have the time or interest in all the details so we packaged up the highlights of the gene therapy series, with some new information and evaluation, too, into one shorter (but not short enough, we know) episode.

"But did you bleed him? - Aesculapius says that bleeding is not a cure. It is only a way of proving that you are a physician at the expense of your patient." Finally, we discuss the EPI-321 epigenetic editing phase I/II clinical trial design and its potential for answering key questions necessary for going to phase III and for providing benefit to participants and patients.

"Good morning, and in case I don't see ya, good afternoon, good evening, and good night!" We take our time to evaluate publicly available preclinical data for EPI-321 used to support the Epicrispr Biotechnology first-in-human gene therapy clinical trial for FSHD. We discuss the data in the context of what is known from other neuromuscular disease gene therapy trials and integrate their own data in respect to what metrics are likely needed to be met for have any chance at providing benefit to patients.

"In the history of science, innovative concepts occasionally arise from sudden left-field inspiration." Here we make sure everyone is up to speed on the types of CRISPR inhibition for FSHD and FSHD epigenetics s that we are all ready to evaluate the preclinical data supporting the Epicrispr Biotechnology EPI321 clinical trial.

"...and by the time they figure out what went wrong, we'll be sitting on a beach, earning twenty percent." This is part 2 of our podcast series covering the important factors in successful gene therapy and introduces the knowledge gained from other neuromuscular diseases and how it can be applied to positively impact gene therapy in FSHD. In part 2, we focus on viral dosing and how it affects therapeutic biodistribution and expression. In addition, we reveal what is known about variable durability of transgene expression and what to look for to predict a durable, or non-durable, therapeutic. Check out the MyFSHD Youtube for the music, as well.

"My friends are toys. I make them. It's a hobby. I'm a genetic designer." This is a two part podcast covering the important factors is successful gene therapy and introduces the knowledge gained from other neuromuscular diseases and how it can be used to positively impact gene therapy in FSHD. In part 1, we focus on AAV serotypes, transgene constructs, immune responses, and delivery. We look into DMD gene therapy and how that can impact the current FSHD gene therapy programs. Check us out on the MyFSHD Youtube channel as well.

"You were seeking some information of some kind?" Continuing our discussion with our young FSHD advocates, asking and answering some questions.

"And that would tell you what is obvious right now? That avoiding apple skins and pizza has no effect on this brutal disease?" Today we discuss the Cure FSHD for All (go to: www.curefshdforall.com) initiative for inclusion of FSHDers under 18 and those with limited mobility into clinical trials and for access to developing therapies.