MyFSHD

"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.

"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.

"You're gonna need a bigger boat." MyFSHD is our summer blockbuster passion project. We discuss how to get it done, whatever your "it" is, in the FSHD space, as well as our trip to Shanghai and Hanoi to continue our efforts to help FSHDers around the world.

"I'll have what she's having." We'll take you through and discuss the recent release of Avidity Biosciences topline results from the phase 1/2 FORTITUDE trial and the preliminary data from the biomarker cohort extension.

"I gotta know what a 5 dollar shake tastes like." We continue our conversation with Tamara Gottlieb, who shares her years of experience helping to keep her family above the FSHD curve and improve quality of life. It's a lot of work, but it can help. Part 2 of 2. Tamara is one of the leaders (along with Emily Ca and Wayne Nesbit) of the "FSHD - supplements, nutrition, and peer support" Facebook gropou, so check it out for more information.

"You are what you eat, and I'm freaking delicious!" Our guest today, Tamara Gottlieb, is the driving force for our First Family of FSHD Fitness, Nutrition, and Lifestyle, and she shares with us what she has learned over her years of experience helping keep her family above the FSHD curve and improve quality of life. It's a lot of work, but it can help. Part 1 of 2. Tamara (along with Emily Ca and Wayne Nesbit) is one of the leaders of the "FSHD - supplements, nutrition, and peer support" Facebook group, so check it out for more information.

"Come on. No, no, don't do that. Don't give me the pouty batface." We have video today (!) for our special guest Carme Farré, who founded FaceToned®, and she shares her experiences as part of an FSHD family and how her techniques for facial fitness can help the FSHD community. If interested, you can arrange a free consultation below:🔗 https://calendly.com/carmefarre/15min?month=2025-04and find more information:🌐 www.facetoned.com📚 courses.facetoned.com

"Never go in against a Sicilian when death is on the line!" We have both survived so far and are back with part 2 of your Reddit questions on FSHD.

"The battle of wits has begun. It ends when you decide and we both drink - and find out who is right, and who is dead." Today Brad, our angry dad, brings a list of your FSHD Reddit questions looking for answers.

"The most valuable commodity I know of is information." Today we discuss current clinical trials in FSHD and the foundational science behind the technology. While NIH has funded much of the foundational science that todays therapeutic approaches are built upon, it is the private individual and foundation support from those with vested interests in a rare disease that drive industry investment that gets the therapies over the line and into the clinic and ultimately to patients.

"Good heavens, are you still trying to win? You've got an over developed sense of vengeance. It's going to get you into trouble someday." We remember Jenny Hasenjaeger and discuss research funding so that we don't let anyone else down.

"You know the Greeks didn't write obituaries. They only asked one question after a man died: 'Did he have passion?'. " Today we are joined by our CRISPR Goddess to discuss her new FSHD optimized gene therapy cassette that is stronger, safer, more compact and all around better than anything out there for use in FSHD and neuromuscular gene therapy approaches.

"Show me the money!" Brad our Angry Dad sits down with us and asks the questions on his mind about the Fulcrum results and others going forward.

"I always tell the truth, even when I lie." Today we are joined by our CRISPR Goddess and cover the Fulcrum Therapeutics REACH phase 3 clinical trial data release and discuss our journey with Fulcrum from the beginning. While very disappointing from several aspects, in the end a lot of benefit truly has been gained for the FSHD field and we are grateful for Fulcrum's contributions to help others going forward. And there are many others coming along, this is the beginning and not the end for FSHD therapeutics.

"There's a time for daring and there's a time for caution, and a wise man understands which is called for." Brad our Angry Dad is back with some questions for us on the Avidity FORTITUDE AOC 1020 phase 1/2 trial interim data report and some muscle building.

"Whatchyou talkin' 'bout Willis?" In a field where every press release is met with unsubstantiated hoopla and proclamations of BREAKTHROUGH! to fire you up to shake you down, we finally have some real news. We provide our evaluation of Avidity's public interim report on their FORTITUDE AOC-1020 phase 1/2 trial.

"You're messing with the wrong guy!!!!" We expand a bit more on the utility of the FSHD-like pig model and then discuss the science behind and implications of p38 inhibition for FSHD.

"We don't get a lot of things to really care about." So, you think you are interested in science, eh? Well, let's see how the sausage is made. Today we share our experience generating the FSHD-like minipig models, which will be key tools for testing and advancing better FSHD therapeutics and developing methods for building back your muscles.

"Come out to the coast, we'll get together, have a few laughs..." The holiday season we discuss the recent FDA approved CRISPR therapy for sickle cell disease and some dynamics of methylation.

"As I leave my competition respirator style, climb the ladder to success escalator style." Today we have the Jaegercast, but first we continue our discussion about apabetalone, a new candidate drug for FSHD.

"I don't know how I'm going to live with myself if I don't stay true to what I believe." We evaluate the recent published work describing apabetalone, a small molecule drug from Resverlogix Corp that has been around for awhile and in clinic for other indications and is now being assessed more seriously as a potential therapeutic for FSHD. Overall, while lacking in some areas, this initial study is generally positive and supports that it is a new candidate worthy of further evaluation.

"I am sick and tired of the entire western world knowing how my kidneys are functioning!" We discuss current and upcoming FSHD clinical trials and touch a little bit on funding.

"Farmer Hoggett knew that little ideas that tickled, and nagged, and refused to go away should never be ignored, for in them lie the seeds of destiny." We are in Australia promoting FSHD awareness with Parliament and to gather government support for FSHD diagnostics and clinical trial infrastructure, as well as catching up with many of our Australian friends.

"Life has meaning only in the struggle. Triumph or defeat is in the hands of God. So let us celebrate the struggle!" With the FDA approval of the first gene therapy for DMD and clinical trials for FSHD in all stages of planning and performance, we take a moment to discuss the history of the DMD gene therapy path to approval as it relates to FSHD and address the important, yet oft ignored, concept of Therapeutic Misconception.

"It's human nature to lie. Most of the time we can't even be honest with ourselves." At MyFSHD is is always FSHD Day. We continue the conversation around therapeutic modalities and clinical trials, hopefully providing additional context for clarification, or just digging a deeper hole. You tell us.

"Apes don't read philosophy." "Yes they do, Otto, they just don't understand it!" We're here to answer your questions and help you understand all things (FSHD) on your mind.

"We can rebuild him. We have the technology. We can make him better than he was. Better, stronger, faster." Today we are at the Biologic Scaffolds for Regenerative Medicine Symposium to discuss novel ways to potentially help FSHDers maintain strength and slow down pathology. Additional technology being presented by be applicable to help regain muscle mass after therapy. Joining us is one of the best FSHD advocates around, Emma Weatherley from FSHD Global Research Foundation in Australia. And we drop the newest track from Jaeger the Kid!

"We Are Unique, Gentlemen, In That We Create Ourselves Through Long Years Of Rigorous Training, Sacrifice, Denial, Pain." Today we focus on our worldwide efforts to help FSHDers everywhere.

Roy: "This is everything, ain't it? This is the choice it comes down to - this is our immortality." Romeo: "You don't need to be thinking immortality - you need to be thinking hit the 7 iron!" Dr Charis Himeda joins us to discuss recent news on stem cells, losmapimod, gene therapy, and antisense for FSHD.

"You just put your pickle on everybody's plate, college boy, and leave the hard stuff to me." We talk a little more about funding, hopefully providing some clarity, then bring on our Angry Dad for some questions, and then bring it home with another new track from Jaeger.

"Sorry, Vern. I guess a more experienced shopper could have gotten more for your seven cents."  Rare disease day is the last day of February, which got us thinking about what really needs to be done to get over the line.  We also answer listener questions about animal models and the Avidity, myostatin inhibition, and cell therapy trials.

"Come on in, grab a beer.  Don't cost nothing."  We have been podcasting about all things FSHD and realize that we have a lot of new listeners over the past year so we want to take this opportunity to catch everyone up on what the MyFSHD podcast is all about.  You may have noticed that we are a bit different.  We are not asking for money and we are not selling you anything, just real talk from experts in all things FSHD to help you understand and navigate the space with knowledge.  On the science side, we discuss a little more Avidity and Vita cell therapy.

"Why, sometimes I've believed as many as six impossible things before breakfast."  Experimental therapies designed specifically for FSHD are finally arriving for trial in the clinic (i.e., in people).  Today we discuss the upcoming Phase 1/2 clinical trial from Avidity using their antibody oligo conjugated siRNA designed specifically to knockdown the DUX4 mRNA in FSHD.

"Do you ever have déjà vu, Mrs. Lancaster?"  "I don't think so, but I could check with the kitchen"  We will discuss some cool new pig data and how we are going about making sure our FSHD-like minipig models will be made right and properly characterized to be useful for testing FSHD therapeutics and muscle building strategies.  As you know, the devil is always in the details and so far pigs are looking pretty darn good!

"I've been going to this high school for 7-1/2 years.  I'm no dummy."  As 2023 gets underway, let's check in and see where the field stands - in our opinion, of course.

"Life isn't like in the movies.  Life..... is much harder."  Whatever you end up doing, love it.  And we love working every day on the problem of FSHD, educating others about the science, helping people learn about themselves, and informing the community of advancements.  We're back and going strong, starting Season 2 with a discussion on the future of clinical trials and therapies, as requested by you.

"Remember no man is a failure who has friends." We catch up with a few friends in this holiday season as FSHD research plows ahead.

"I want four fried chickens and a Coke".  Dr. Charis Himeda joins us as we discuss some encouraging recent data from Sarepta for one of their DMD gene therapy trials and from Avidity for their myotonic dystrophy phase I/II trial and how it all potentially impacts FSHD.  In addition, we revisit the potential (or lack there of) for placental or umbilical cord derived stem cell therapy for FSHD.

"Never mind manoeuvres, always go at them". Dr. Bob Bloch from the University of Maryland School of Medicine joins us to discuss his development of the human FSHD muscle xenograft mouse model that is a key tool in the pre-clinical testing pipeline for FSHD therapeutics and biomarker discovery.

"You're messing with the wrong guy!"  Happy Thanksgiving to our friends in the US, and for everyone else, it is always a good time to remember and give thanks for those you care about and who care about you.  For us, that is the worldwide FSHD community.  Today we have Brad, our angry dad, and discuss accessibility issues for safety and dealing with roadblocks in research.