Evaluating gene expression data in FSHD and presenting at ASGCT

"Well, ain't we a pair, raggedy man." Today we go through our Sydney FSHD Community Day presentation (with a little extra) for FSHD Global Research Foundation, updating the FSHD epigenetic saliva testing and discussing different therapeutic approaches going to clinical trial for FSHD.

"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.