Imagine if your abilities to
hug your parents,
smile at your friend’s terrible jokes,
dance at your wedding, and
shower independently
were stolen away day after day.
How much urgency would fuel you?
Heloise Hoffmann - FSHD patient
"As a young child, I lived the life of my dreams. Nothing could top the freedom I felt hitting a ball on the tennis courts or from the wind blowing through my hair atop a horse.
But, when I was ten years old, odd symptoms started to wrack my body - stumbling suddenly and dropping my racquet randomly on the courts, contorted and inflamed shoulders for
weeks after just mild exercise, daily debilitating pain,...
A wild goose chase for an answer quickly ensued lasting three years, replete with prodding and poking and examining until my verdict came
at thirteen years old: facioscapulohumeral muscular dystrophy."
What is FSHD?
The clock is ticking. Every day, facioscapulohumeral muscular dystrophy (FSHD) steals the muscles, livelihoods, and independence of almost one million people worldwide.[1]
FSHD is a rare neuromuscular disorder causing progressive and highly variable loss of skeletal muscle.
Despite its name, FSHD can progress to affect any skeletal muscle in the body, most commonly the muscles
of the face, arms, shoulders, and legs.
Typical symptoms include difficulty raising arms, foot drop,
scapular winging, and debilitating pain and fatigue.[1] However, one of the challenges of FSHD is that it
presents very differently in each patient; for some, getting around without a wheelchair is an impossible
task, while others are unable to smile or hug due to facial weakness and limited range of motion.[2]
Illustration of muscles that could be affected by FSHD. Source: Banerji & Zammit EMBO Mol Med 2021)
A subset of patients experience early-onset FSHD, in which symptoms appear before 10 years old, accompanied by extremely rapid and severe progression. Kids with FSHD often experience additional decline in breathing, sight, and hearing.[3] In some cases, breathing complications and severe falls linked to FSHD can even cause premature death.[4]
Learn more about what the life of an FSHD patient looks like in this short documentary made by Lexi Pappas.
There is currently no cure for FSHD, but there is hope!
"The words ‘deteriorating muscles’, ‘progressive weakness’, and ‘no cure’
were dropped casually in my lap, worming their way into and completely shattering the life I had
pictured for myself.
For the next two years, my mental health went completely down the drain as
I wrestled to digest but instead rejected my diagnosis. A million questions pried their way into
my life: Will I be in a wheelchair?
Will I be able to hold my future children?
Will I be able to
live independently as an adult?"
Heloise Hoffmann - FSHD Patient
What causes FSHD?
The root cause of FSHD is the aberrant expression of a gene called DUX4, which is typically silent in healthy people. Two distinct genetic mutations can cause FSHD (FSHD1 and FSHD2), but both genetic types ultimately result in the expression of DUX4 and are linked to the same muscle loss phenotype seen in FSHD.[1]
DUX4 encodes a protein in the family of transcription factors, which are responsible for regulating gene expression. Typically, DUX4 is briefly expressed in an early stage of embryogenesis in order to regulate development, but it becomes heavily repressed and silenced soon thereafter. When expressed in adults, DUX4 activates a cascade of hundreds of typically silent target genes, which, through a complex mechanism, cause degradation of skeletal muscle fibers.[5]
Healthy muscle versus FSHD muscle. Source: Banerji & Zammit EMBO Mol Med 2021
"In just a few short years, FSHD has already stolen many of my abilities since my diagnosis. And yet, I am more optimistic than ever about a treatment. Though I don’t think I can ever grow to embrace my diagnosis, I have resolved to do everything in my power to stop FSHD from stopping me - because although I have FSHD, it doesn't have me."
That's why we are trailblazing the way for a new treatment approach for FSHD.
Where does dux. come in?
The DUX4 transcription factor is composed of two main parts:
the DNA-binding domain (DBD) and transcriptional activator domain (TAD).
The DBD identifies and binds to certain patterns of DNA, defining the DUX4
target sequences, and the TAD is responsible for activating those target genes.
Previous work suggests that without both working parts, DUX4 can’t perform its
pathogenic function.[6][7]
Our approach is elegant yet simple: overexpression of a modified form of just the DBD portion of the DUX4 protein (named DUX4-DBD), which binds to the same sites that the pathogenic DUX4 would bind to. By competing for binding sites, DUX4-DBD prevents toxic, full-length DUX4 from activating its targets and hence suppresses the pathogenic pathway that would lead to muscle degradation in people with FSHD. In addition, we are modulating the components of our DUX4-DBD construct to boost its migratory potential within muscle fibers and maximize its edge as a suppressor of genes activated by DUX4.
dux. is just the start. Our team is forging a new class of FSHD therapeutics based solely on human proteins, with plans to deliver our package via AAV9 to bring much-needed, immediate treatment options for FSHD. Ultimately, we hope to ride on the forefront of muscle stem cell innovation to design an all-in-one regenerative therapy.
References.
[1] Statland JM, Tawil R. Facioscapulohumeral muscular dystrophy. Continuum 2016, 22, 1916–1931. doi: 10.1212/CON.0000000000000399.
[2] Ghasemi M, Emerson CP, Hayward LJ. Outcome Measures in Facioscapulohumeral Muscular Dystrophy Clinical Trials. Cells 2022, 11(4), 687; https://doi.org/10.3390/cells11040687
[3] Chen TH, Wu YZ, Tseng YH. Early-Onset Infantile Facioscapulohumeral Muscular Dystrophy: A Timely Review. Int. J. Mol. Sci. 2020, 21(20), 7783; https://doi.org/10.3390/ijms21207783
[4] Simonds AK. Respiratory complications of the muscular dystrophies. Semin Respir Crit Care Med. 2002 Jun;23(3):231-8. Click here to read Abstract.
[5] Mocciaro E, Runfola V, Ghezzi P, Pannese M, Gabellini D. DUX4 Role in Normal Physiology and in FSHD Muscular Dystrophy. Cells. 2021 Nov 26;10(12):3322. doi: 10.3390/cells10123322. PMID: 34943834; PMCID: PMC8699294.
[6] Lee, J. K., Bosnakovski, D., Toso, E. A., Dinh, T., Banerjee, S., Bohl, T. E., … Aihara, H. (2018). Crystal Structure of the Double Homeodomain of DUX4 in Complex with DNA. Cell Reports, 25(11), 2955-2962.e3. doi: 10.1016/j.celrep.2018.11.060
[7] Mitsuhashi, H., Ishimaru, S., Homma, S., Yu, B., Honma, Y., Beermann, M. L., & Miller, J. B. (2018). Functional domains of the FSHD-associated DUX4 protein. Biology Open, 7(4). doi: 10.1242/bio.033977
