Defining Transcription Regulatory Elements in the Human Frataxin Gene: Implications for Gene Therapy.

Human Gene Therapy
Jixue LiMarek Napierala

Abstract

Friedreich's ataxia (FRDA) is the most common inherited form of ataxia in humans. It is caused by severe downregulation of frataxin (FXN) expression instigated by hyperexpansion of the GAA repeats located in intron 1 of the FXN gene. Despite numerous studies focused on identifying compounds capable of stimulating FXN expression, current knowledge regarding cis-regulatory elements involved in FXN gene expression is lacking. Using a combination of episomal and genome-integrated constructs, we defined a minimal endogenous promoter sequence required to efficiently drive FXN expression in human cells. We generated 19 constructs varying in length of the DNA sequences upstream and downstream of the ATG start codon. Using transient transfection, we evaluated the capability of these constructs to drive FXN expression. These analyses allowed us to identify a region of the gene indispensable for FXN expression. Subsequently, selected constructs containing the FXN expression control regions of varying lengths were site specifically integrated into the genome of HEK293T and human-induced pluripotent stem cells (iPSCs). FXN expression was detected in iPSCs and persisted after differentiation to neuronal and cardiac cells, indicating lineage ...Continue Reading

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Citations

Jul 10, 2020·Human Gene Therapy·Dongsheng Duan
Nov 20, 2020·Molecular Therapy. Methods & Clinical Development·Brahim BelbellaaHélène Puccio
Jan 13, 2021·Human Molecular Genetics·Layne N RoddenSanjay I Bidichandani

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Methods Mentioned

BETA
PCR
transfection
acetylation

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