Ignite Creation Date:
2024-05-06 @ 3:18 PM
Last Modification Date:
2024-10-26 @ 1:46 PM
Study NCT ID:
NCT04580979
Status:
COMPLETED
Last Update Posted:
2024-03-08
First Post:
2020-10-02
Brief Title:
Natural History Study of FDXR Mutation-related Mitochondriopathy
Sponsor:
State University of New York at Buffalo
Organization:
State University of New York at Buffalo
Study Overview
Official Title:
A Natural History Study of Neurodegeneration and Optic Atrophy Caused by Ferredoxin Reductase Mutations in Pediatric and Adult Patients
Status:
COMPLETED
Status Verified Date:
2024-03
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
The purpose of the study is to systematically characterize the clinical course of the progressive neuropathy and optic atrophy observe in pediatric and adult patients with biallelic mutations in the ferredoxin reductase gene
Detailed Description:
The mitochondrial membrane-associated ferredoxin reductase FDXR is a flavoprotein that initiates the mitochondrial electron transport chain by transferring electrons from NADPH to the mitochondrial cytochrome P450 system via the ferredoxins FDX1 or FDX2 In addition to essential roles in Fe-S cluster biogenesis this pathway is also central to the biosynthesis of steroid hormones Previously Dr Taosheng Huangs research group has identified mutations in the FDXR gene in many individuals who share clinical presentations consistent with a mitochondrial disorder-including ataxia hypotonia and optic atrophy-and obtained a naturally-occurring Fdxr mutant mouse model from Jackson Lab that corroborated these results PMID 29040572 and PMID 30250212 In particular FDXR enzyme activity mitochondrial complex activities and ATP production were all significantly reduced in their patient samples Their studies further indicated that Fdxr mutation leads to neurodegeneration that is associated with both inflammation as well as the abnormal accumulation of iron in the mitochondria likely as a result of disrupted Fe-S cluster synthesis More recently his group has used the CRISPR-Cas9 system to generate a mouse line with a pR389W amino acid change which more precisely matches the most common human variant observed in their patients and shows a much more severe phenotype than their previous naturally occurring Fdxr mouse model They have also show that AAV-based gene therapy can significantly improve the condition of Fdxr mutant mice DOIhttpsdoiorg101016jomtm202005021 providing valuable preclinical data that may open the door for adapting such gene therapy treatments for use in human clinical trials Given the recent regulatory approval granted to gene therapy treatments for LCA2 SMA1 and β-thalassemia there is strong possibility that such an approach will ultimately produce a viable clinical treatment for FDXR patients as well
FDXR is required for Iron-sulfur Fe-S clusters synthesis which is essential for multiple important biological processes including electron transfer cofactor synthesis and gene regulation Fe-S cluster biosynthesis is a tightly regulated process that requires coordinated delivery of both iron and sulfur and is a cofactor of many proteins A variety of human disorders have been associated with impaired Fe-S cluster synthesis including neurodegenerative disorders eg Friedreichs ataxia and myopathy with lactic acidosis Iron homeostasis which requires precise synthesis and localization of Fe-S clusters in mitochondria is critical to ensure that there is sufficient iron for cellular functions without reaching toxic levels of iron Excessive levels of iron favor the formation of excess oxygen free radicals and consequent mitochondrial dysfunction
The Rare Disease Act and Rare Disease Orphan Product Development Act highlight the importance of rare disease research and the obstacles to developing effective treatments for these diseases However the study of rare diseases may open a window to studying other human conditions For example Iron-sulfur biosynthesis abnormalities have been observed in more common human diseases such as Friedreichs ataxia This relationship highlights the importance of human disease research by multiple approaches to understand biological mechanisms and for general application to human health For these reasons a better understanding of the pathogenesis of FDXR deficiency may help facilitate our knowledge of disease biology neurodevelopment brain function and other organ abnormalities Thus in order to better understand the function of FDXR and to help lay the groundwork for eventual clinical trials of gene therapy or drug-based treatments for FDXR-related disease the investigators propose this natural history study of both pediatric as well as adult patients with biallelic mutations in the ferredoxin reductase gene
FDXR is required for Iron-sulfur Fe-S clusters synthesis which is essential for multiple important biological processes including electron transfer cofactor synthesis and gene regulation Fe-S cluster biosynthesis is a tightly regulated process that requires coordinated delivery of both iron and sulfur and is a cofactor of many proteins A variety of human disorders have been associated with impaired Fe-S cluster synthesis including neurodegenerative disorders eg Friedreichs ataxia and myopathy with lactic acidosis Iron homeostasis which requires precise synthesis and localization of Fe-S clusters in mitochondria is critical to ensure that there is sufficient iron for cellular functions without reaching toxic levels of iron Excessive levels of iron favor the formation of excess oxygen free radicals and consequent mitochondrial dysfunction
The Rare Disease Act and Rare Disease Orphan Product Development Act highlight the importance of rare disease research and the obstacles to developing effective treatments for these diseases However the study of rare diseases may open a window to studying other human conditions For example Iron-sulfur biosynthesis abnormalities have been observed in more common human diseases such as Friedreichs ataxia This relationship highlights the importance of human disease research by multiple approaches to understand biological mechanisms and for general application to human health For these reasons a better understanding of the pathogenesis of FDXR deficiency may help facilitate our knowledge of disease biology neurodevelopment brain function and other organ abnormalities Thus in order to better understand the function of FDXR and to help lay the groundwork for eventual clinical trials of gene therapy or drug-based treatments for FDXR-related disease the investigators propose this natural history study of both pediatric as well as adult patients with biallelic mutations in the ferredoxin reductase gene
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None