by Jamshid Arjomand, PhD, Chief Science Officer, FSHD Society
Our original plan for 2020 was to host the International Research Congress (IRC) in Washington, DC, in proximity to the FDA and the National Institutes of Health. The US capital (in an election year, no less!) would have provided an additional level of excitement to researchers traveling from all over the globe. But with the COVID-19 pandemic restricting both domestic and international travel, we had to look for alternatives.
Canceling the meeting was never an option. The dissemination of the latest scientific discoveries was simply too important to skip. The FSHD Society’s IRC program committee urged us to plan for a full two-day virtual meeting, and assured us: “If you build it, they will come!” To our immense relief and delight, the meeting, held June 25-26, drew a record 280 participants, nearly 100 more than any previous IRC. Many were first-timers. The program was as impressive as ever, clearly demonstrating that researchers were eager to share their findings.
The meeting began with a thoughtful introspective from Dr. George Padberg covering his illustrious career on FSHD (see our blog post). This was followed by two half-days of presentations ranging from early discovery research in cells and animals to studies involving patients and efforts to develop treatments.
Many possible ways that DUX4 can damage muscles
While researchers broadly agree that the DUX4 gene is central to FSHD, questions remain about how it leads to muscle dysfunction and degeneration. Peter Zammit’s lab at King’s College London, UK, reported that FSHD muscle is able to regenerate, but not well enough to maintain healthy structure and function. According to data from Julie Dumonceaux at University College London, UK, DUX4 may kill muscle cells through a process called “necroptosis” (a regulated, inflammatory mode of cell death). At the University of Minnesota, Minneapolis, Michael Kyba’s lab, using mice in which DUX4 can be turned on and off, examined whether DUX4 could self-propagate its expression. Although a “feed-forward” mechanism for DUX4 expression was not detected, the researchers observed that some of the pathological changes continued to progress even after DUX4 had been shut off. Katherine Williams from the University of California, Irvine, reported that DUXA, a gene activated by DUX4, can perpetuate the abnormal gene program initiated by DUX4, even after DUX4 is no longer present. These findings highlight the complex chain of events triggered by DUX4 misexpression, as well as novel points of intervention for therapeutic development.
Studies of the FSHD population yielded fascinating observations. Peter Lunt mined the published literature for correlations among traits that might influence disease severity, and reported earlier disease onset in individuals who had inherited FSHD through a maternal lineage (grandmother to mother) relative to a paternal (grandfather to father) mode of transmission. Christopher Banerji at King’s College London analyzed the UK patient registry with 643 patients and described four clinical presentations of FSHD1. While the majority (74%) exhibited classic signs of muscle weakness starting from the upper to lower body, the remaining groups exhibited signs of facial sparing with different degrees of body or leg muscle involvement. The study also found that pregnancies were associated with slower onset and progression, in contrast with personal accounts from women who felt pregnancies and childbirth aggravated their FSHD symptoms. More research is clearly needed to better elucidate the role of gender in inheritance, progression, and severity of FSHD.
Biomarkers, therapies, and the future
In the realm of therapy development, one of the holy grails is a “biomarker” – an FSHD-associated molecule detectable in patients’ muscles or blood, whose levels correlate with a drug’s activity or with the severity of symptoms. Maria Traficante from Robert Bloch’s lab at the University of Maryland School of Medicine, Baltimore, presented data from their mouse model of FSHD in which a human DUX4-regulated protein called SLC34A2 was detectable in both muscle and blood of these mice, suggesting a possible candidate biomarker of DUX4 activity. Lucienne Ronco of Fulcrum Therapeutics presented data of several DUX4-regulated gene candidates identified from MRI-informed muscle needle biopsies. These markers are being tracked in the ongoing ReDUX4 Phase 2 clinical trial.
Several groups discussed advances in therapeutic approaches targeting DUX4 transcripts directly. Yi-Wen Chen of Children’s National Hospital in Washington, DC, and Rika Maruyama of the University of Alberta, Edmonton, described their progress with modified chemistry of antisense oligonucleotides designed for better stability (see article in FSH Watch, 2017, Issue 3). When these molecules were injected into a mouse model of FSHD (FLExDUX4 from the lab of Peter and Takako Jones), the mice had increased grip strength and reduced scar-like tissue in their FSHD-affected muscles. Lindsay Wallace from Scott Harper’s lab at Nationwide Children’s Hospital, Columbus, Ohio, reported new data from a different mouse model (TIC-DUX4) that was treated with their experimental gene therapy. The mice showed long-term improvements in function and muscle tissue. In addition, Wallace summarized an additional study in mice, supporting the safe use of the lab’s gene therapy at clinically relevant doses. Another DUX4-silencing approach was given by Afrooz Rashnonejad, also from Scott Harper’s lab. She reported on the development of a gene editing system, CRISPR-As13b, designed to silence DUX4 expression without cutting DNA, which could otherwise lead to unwarranted side effects.
This year’s industry panel included participants from several new companies entering the FSHD field. Romesh Subramanian from Dyne Therapeutics and Anthony Saleh of miRecule discussed their companies’ approach and progress for delivering therapeutics using antibodies directly to muscles. Fulcrum Therapeutics’ Michelle Mellion provided an overview of their commitment to FSHD and the ongoing ReDUX4 clinical trial with losmapimod (see our blog update). “Big pharma” was represented by Jane Owens from Pfizer, who highlighted some of their exploratory efforts to establish relevant cell assays for FSHD.
The meeting concluded with the recognition of three remarkable young investigators in the field of FSHD research (see our blog post), as well as an award for the best poster to Darina Sikrova, Leiden University Medical Center, Netherlands, and Kohei Hamanaka, National Institute of Neuroscience, Japan.
It is often said that “necessity is the mother of invention,” but without a supportive community, even the best-laid plans cannot materialize. We are grateful to the 2020 IRC Program Committee for suggesting a comprehensive virtual meeting, and to the global research community for embracing the video conferencing platform and sharing their discoveries. The meeting wouldn’t have been possible without the generous support from our sponsors. Although we certainly hope to be able to host an in-person IRC next year in Leiden, Netherlands, we will continue to offer a virtual component of the IRC to ensure the broadest global participation.
Editor’s note
A more technical summary of the meeting has been submitted to the journal Skeletal Muscle and will be linked to the FSHD Society’s website upon publication.
Antisense oligonucleotides are far from an ideal treatment from the patient’s perspective. AONs cannot be taken orally or injected into a blood vessel, but rather injected directly into the muscle tissue. AONs would need to be injected at regular intervals. AONs are long, complex molecules that are extremely slow and expensive to manufacture. A single dose of AONs could cost tens or even hundreds of thousands of dollars.
Take a look at the treatment regimen and cost of Spinraza, an AON therapy for SMA. Yikes! Not what most of us are hoping for!
A (relatively) cheap, easy, oral medication like Losmapimod is much preferable to AONs. But while AONs can cut DUX4 production up to 99%, a drug that works indirectly, like Losmapimod, might only reduce it 50-75%. Losmapimod may only *slow* rather than *stop* FSHD.
Perhaps the answer is a combination of something like Losmapimod with another treatment that mitigates the downstream effects of DUX4 (e.g. anti-oxidants or anti-inflammatories)?