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Research Update: SELENON

Updated: Jun 4

A scientist in the Zito lab preparing an experiment.

We are honored to support groundbreaking discoveries related to SELENON-Related Disorders, thanks to our generous donors and advocacy partners.


Ana Ferreiro, implementing biomarkers and high-throughput screening to identify and evaluate repurposing drugs for treating SELENON-RM. Funding: 2023-2024. Co funded with Giving Strength.

Research efforts in the last few years have given us a better understanding of this CMD subtype, and how to target SELENON-related muscle dysfunction for treatment. However, scientists have yet to identify a biomarker that would make testing of potentially beneficial drugs easier. Biomarkers are biological indicators of a disease process, important in measuring changes in the body caused by disease or a potential treatment. This project aims to establish reliable biomarkers and screening methods to close this critical research gap.

Using cells cultivated from SELENON-affected individuals as well as a SELENON mouse model, the Ferreiro Lab has identified two promising biomarkers that reveal the association between Endoplasmic Reticulum (ER) stress and bioenergetic deficiency, a key dysfunction in people with SELENON-Related Disorders, which could be used to aid in clinical management and future treatments.

The team is also optimizing a high-throughput drug screening approach, to provide a new avenue for therapeutic exploration. Using these newly discovered biomarkers with patient-derived cell cultures, they are now screening over 600 drugs already approved by the FDA for other conditions. If any of these drugs show positive biomarker signals, they would be strong candidates for drug repurposing, extending the original indication to include use in SELENON-RM.


Ester Zito, Inhibition of the endoplasmic reticulum oxidase ERO1 alpha as a strategy to treat SELENON-RM. Funding: 2023-2024. Co funded with Giving Strength.

Meticulous work at the Zito Lab has significantly contributed to uncovering a mechanism that controls oxidative stress, calcium dynamics and the bioenergetic deficiency that causes muscle function impairment in SELENON-RM. In this March 2024 publication, the team demonstrated that SELENON interacts with the enzyme ERO1A in a counterbalancing fashion to maintain muscle homeostasis. When SELENON is absent or defective, ERO1A goes out of control, inducing more oxidative stress and triggering calcium dysregulation and energetic imbalance, which is detrimental to muscle function. The team has discovered that a drug, called TUDCA, may inhibit ERO1A activity, and has shown functional improvement in mouse and cell models. This indicates that ERO1A is both a potential biomarker and a viable target for pharmacological intervention.

The research team is now studying the potential of ERO1A as a suitable biomarker by measuring whether ERO1A levels correlate with disease severity, using muscle samples from affected individuals with a variety of mutations. Additionally, they are developing novel ERO1A inhibitors to measure potential therapeutic effect in the mouse model. Suppressing the muscle defect in mice treated with these inhibitors may provide a rationale for human clinical trials in SELENON-RM.


Nicol Voermans, Natural history, outcome measures and trial readiness in LAMA2-related muscular dystrophy and SELENON-related myopathy in children and adults: The LAST STRONG study. Funding: 2023-2025. Co funded with Prinses Beatrix Spier Fonds and Stichting Voor Sara.

As we expand our understanding of SELENON-RM and LAMA2-RD and make progress in the discovery of potential treatments, natural history data and outcome measures important for clinical trials are lacking. In 2020, Dr. Voerman’s team launched the LAST STRONG Study, a 1.5-year project to collect natural history data from affected individuals (27 with LAMA2-RD and 11 with SELENON-RM), ages 3 to 50 years.

With support from our three organizations, the study has now been extended, aiming to analyze and publish all follow-up data, and select outcome measures that are sensitive, patient friendly, and sustainable. Baseline results have been published, including decreased bone quality leading to fragility fractures and impaired pulmonary function. The team will now assess the pathophysiology of decreased bone mineral density, correlation of neurocognitive functioning with brain MRI, quality of life, affected individuals’ expectations about clinical trials, biomarkers, and the collection of skin and muscle biopsies. Altogether, this work will contribute to implementation of improved clinical care and future clinical trials.


SELENON Genetic Prevalence Estimate

Thanks to our grant from the Chan Zuckerberg Initiative’s Rare as One Project, Cure CMD was invited to submit two recessive genes to the Broad Institute’s Rare Genomes Project to calculate estimated global prevalence. Using the Broad Institute’s Genome Aggregation Database (gnomAD), the largest human reference database containing genetic data from more than 140,000 contributors, scientists were able to use genetic data from participants in the Congenital Muscle Disease International Registry and The Beggs Lab to estimate the frequency of SELENON-RM. Calculations indicate that there are approximately 12,000 affected individuals worldwide, and an estimated 520 in the United States.

Since performing this calculation, the Broad team has created an open access tool called GeniE, with the results of SELENON frequency calculations now publicly accessible.

Among diverse applications, this prevalence estimate can now be used to attract industry investors. Cure CMD is grateful to CZI for the opportunity, and the Broad Institute for providing this additional tool to advance treatment development for SELENON-Related Disorders.


Learn more about SELENON-Related Disorders on MDA’s recent blog post, Simply Stated: Updates in SELENON (SEPN1)-Myopathy, and on Cure CMD’s SELENON information page. You can also check out Cure CMD’s Research Funding Portfolio to learn about other projects we’ve funded, and our research strategy for the CMD’s.


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