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

doi:10.1186/s13023-021-02048-0

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 journal › Review article › peer-review

12 Citations (Scopus)

28 Downloads (Pure)

Abstract

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We provide an overview of the 21 published SSMD cases and have compiled additional sequencing data for four previously unpublished individuals to illustrate the genetic component of SSMD, and the role of sequencing data in diagnosis.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 language	English
Article number	446
Number of pages	15
Journal	Orphanet Journal of Rare Diseases
Volume	16
Issue number	1
DOIs	https://doi.org/10.1186/s13023-021-02048-0
Publication status	Published - 23 Oct 2021
Externally published	Yes

Keywords

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

Access to Document

10.1186/s13023-021-02048-0Licence: CC BY

s13023-021-02048-0Final published version, 2.26 MBLicence: CC BY

Cite this

@article{6b745fb6fdc04b0497720f301a986829,

title = "Development of therapies for rare genetic disorders of GPX4: roadmap and opportunities",

abstract = "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.",

keywords = "Sedaghatian-type spondylometaphyseal dysplasia, SSMD, Glutathione peroxidase 4, GPX4, Rare genetic disorder, Therapy development, Roadmap, Ultra-rare disease",

author = "Cheff, {Dorian M} and Muotri, {Alysson R.} and Stockwell, {Brent R} and Schmidt, {Edward E.} and Qitao Ran and Kartha, {Reena V} and Johnson, {Simon C} and Plavi Mittal and Arn{\'e}r, {Elias S. J.} and Wigby, {Kristen M.} and Hall, {Matthew D.} and Ramesh, {Sanath Kumar}",

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.",

year = "2021",

month = oct,

day = "23",

doi = "10.1186/s13023-021-02048-0",

language = "English",

volume = "16",

journal = "Orphanet Journal of Rare Diseases",

issn = "1750-1172",

publisher = "BioMed Central",

number = "1",

}

TY - JOUR

T1 - Development of therapies for rare genetic disorders of GPX4

T2 - roadmap and opportunities

AU - Cheff, Dorian M

AU - Muotri, Alysson R.

AU - Stockwell, Brent R

AU - Schmidt, Edward E.

AU - Ran, Qitao

AU - Kartha, Reena V

AU - Johnson, Simon C

AU - Mittal, Plavi

AU - Arnér, Elias S. J.

AU - Wigby, Kristen M.

AU - Hall, Matthew D.

AU - Ramesh, Sanath Kumar

N1 - 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.

PY - 2021/10/23

Y1 - 2021/10/23

N2 - 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.

AB - 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.

KW - Sedaghatian-type spondylometaphyseal dysplasia

KW - SSMD

KW - Glutathione peroxidase 4

KW - GPX4

KW - Rare genetic disorder

KW - Therapy development

KW - Roadmap

KW - Ultra-rare disease

U2 - 10.1186/s13023-021-02048-0

DO - 10.1186/s13023-021-02048-0

M3 - Review article

C2 - 34688299

SN - 1750-1172

VL - 16

JO - Orphanet Journal of Rare Diseases

JF - Orphanet Journal of Rare Diseases

IS - 1

M1 - 446

ER -

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

Abstract

Keywords

Access to Document

Fingerprint

Cite this