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

Humans Osteochondrodysplasias Rare Diseases / genetics
GPX4 Glutathione peroxidase 4 Rare genetic disorder Roadmap SSMD Sedaghatian-type spondylometaphyseal dysplasia Therapy development Ultra-rare disease

Journal

Orphanet journal of rare diseases
ISSN: 1750-1172
Titre abrégé: Orphanet J Rare Dis
Pays: England
ID NLM: 101266602

Informations de publication

Date de publication:
23 10 2021
Historique:
received: 06 04 2021
accepted: 19 09 2021
entrez: 24 10 2021
pubmed: 25 10 2021
medline: 3 11 2021
Statut: epublish

Résumé

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. 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We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis.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. 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.

Sections du résumé

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.

Identifiants

DOI: 10.1186/s13023-021-02048-0 PMID: 34688299 PMC: PMC8542321
pubmed: 34688299
doi: 10.1186/s13023-021-02048-0
pii: 10.1186/s13023-021-02048-0
pmc: PMC8542321
doi:

Types de publication

Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Review

Langues

eng

Sous-ensembles de citation

IM

Pagination

446

Informations de copyright

© 2021. The Author(s).

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Auteurs

Dorian M Cheff (DM)

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
ORCID: 0000-0003-2422-2268

Alysson R Muotri (AR)

Department of Pediatrics, University of California, San Diego, San Diego, CA, USA.
Department of Cellular and Molecular Medicine, University of California, San Diego, San Diego, CA, USA.

Brent R Stockwell (BR)

Department of Biological Sciences, Columbia University, New York, NY, USA.
Department of Chemistry, Columbia University, New York, NY, USA.

Edward E Schmidt (EE)

Department of Microbiology and Immunology, Montana State University, Bozeman, MT, USA.

Qitao Ran (Q)

Department of Cell Systems and Anatomy, University of Texas Health Science Center, San Antonio, San Antonio, TX, USA.
Research and Development Service, South Texas Veterans Health Care System, San Antonio, TX, USA.

Reena V Kartha (RV)

Department of Experimental and Clinical Pharmacology, Center for Orphan Drug Research, College of Pharmacy, University of Minnesota, Minneapolis, MN, USA.

Simon C Johnson (SC)

Department of Neurology, University of Washington, Seattle, WA, USA.
Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, WA, USA.
Center for Integrative Brain Research, Seattle Children's Research Institute, Seattle, WA, USA.

Plavi Mittal (P)

In-Depth Genomics, Bellevue, WA, USA.

Elias S J Arnér (ESJ)

Division of Biochemistry, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 77, Stockholm, Sweden.
Department of Selenoprotein Research, National Institute of Oncology, Budapest, 1521, Hungary.

Kristen M Wigby (KM)

Department of Pediatrics, Division of Genetics, San Diego and Rady Children's Hospital-San Diego, University of California, San Diego, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.

Matthew D Hall (MD)

National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.

Sanath Kumar Ramesh (SK)

CureGPX4.org, Seattle, WA, USA. sanath@GPX4.org.

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