Development of therapies for rare genetic disorders of GPX4: roadmap and opportunities

Dorian M. Cheff, Alysson R. Muotri, Brent R. Stockwell, Edward E. Schmidt, Qitao Ran, Reena V. Kartha, Simon C. Johnson, Plavi Mittal, Elias S.J. Arnér, Kristen M. Wigby, Matthew D. Hall, Sanath Kumar Ramesh

Research output: Contribution to journalReview articlepeer-review

11 Scopus citations


Background: Extremely rare progressive diseases like Sedaghatian-type Spondylometaphyseal Dysplasia (SSMD) can be neonatally lethal and therefore go undiagnosed or are difficult to treat. Recent sequencing efforts have linked this disease to mutations in GPX4, with consequences in the resulting enzyme, glutathione peroxidase 4. This offers potential diagnostic and therapeutic avenues for those suffering from this disease, though the steps toward these treatments is often convoluted, expensive, and time-consuming. Main body: The CureGPX4 organization was developed to promote awareness of GPX4-related diseases like SSMD, as well as support research that could lead to essential therapeutics for patients. We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis. We outline in detail the steps CureGPX4 has taken to reach milestones of team creation, disease understanding, drug repurposing, and design of future studies. Conclusion: The primary aim of this review is to provide a roadmap for therapy development for rare, ultra-rare, and difficult to diagnose diseases, as well as increase awareness of the genetic component of SSMD. This work will offer a better understanding of GPx4-related diseases, and help guide researchers, clinicians, and patients interested in other rare diseases find a path towards treatments.

Original languageEnglish (US)
Article number446
JournalOrphanet Journal of Rare Diseases
Issue number1
StatePublished - Dec 2021

Bibliographical note

Funding Information:
Open Access funding provided by the National Institutes of Health (NIH). This work was supported through financial contributions from CureGPX4 organization, a part of Care and Share, a 501(c)(3) non-profit organization, and in part by the Intramural research program of the NCATS, NIH.

Funding Information:
We thank the Technology Ventures office at Columbia University for donating their time to create the collaboration network CDA.

Publisher Copyright:
© 2021, The Author(s).


  • GPX4
  • Glutathione peroxidase 4
  • Rare genetic disorder
  • Roadmap
  • SSMD
  • Sedaghatian-type spondylometaphyseal dysplasia
  • Therapy development
  • Ultra-rare disease


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