Future Prospects of Gene Therapy for Friedreich’s Ataxia

Ocana-Santero, Gabriel; Díaz‐Nido, Javier; Herranz-Martín, Saúl

doi:10.3390/ijms22041815

Cited by 42 publications

(37 citation statements)

References 107 publications

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“…GAA-repeat mice models have the advantage of mimicking the most common mutation found in patients (the GAA expansion). Nevertheless, all the GAA-repeat models developed to date present a mild phenotype, suggesting that the frataxin expression in these models is above (or slightly below) the pathological threshold required to trigger FA-like phenotypes in mice (reviewed in [ 47 , 48 ]. This limits its usefulness as a model to study the pathophysiology of the disease and also to test new therapeutic approaches, as no clear biomarkers of disease severity can be defined.…”

Section: Discussionmentioning

confidence: 99%

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Medina-Carbonero

Sanz-Alcázar

Britti

et al. 2022

Cell. Mol. Life Sci.

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Friedreich Ataxia (FA) is a rare neuro-cardiodegenerative disease caused by mutations in the frataxin (FXN) gene. The most prevalent mutation is a GAA expansion in the first intron of the gene causing decreased frataxin expression. Some patients present the GAA expansion in one allele and a missense mutation in the other allele. One of these mutations, FXNI154F, was reported to result in decreased content of mature frataxin and increased presence of an insoluble intermediate proteoform in cellular models. By introducing this mutation into the murine Fxn gene (I151F, equivalent to human I154F) we have now analyzed the consequences of this pathological point mutation in vivo. We have observed that FXNI151F homozygous mice present low frataxin levels in all tissues, with no evidence of insoluble proteoforms. Moreover, they display neurological deficits resembling those observed in FA patients. Biochemical analysis of heart, cerebrum and cerebellum have revealed decreased content of components from OXPHOS complexes I and II, decreased aconitase activity, and alterations in antioxidant defenses. These mitochondrial alterations are more marked in the nervous system than in heart, precede the appearance of neurological symptoms, and are similar to those observed in other FA models. We conclude that the primary pathological mechanism underlying the I151F mutation is frataxin deficiency, like in patients carrying GAA expansions. Therefore, patients carrying the I154F mutation would benefit from frataxin replacement therapies. Furthermore, our results also show that the FXNI151F mouse is an excellent tool for analyzing tissue-specific consequences of frataxin deficiency and for testing new therapies.

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Section: Discussionmentioning

confidence: 99%

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Medina-Carbonero

Sanz-Alcázar

Britti

et al. 2022

Cell. Mol. Life Sci.

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“…Consequently, it is not surprising that mitochondrial function is compromised in many diseases, particularly those associated with high-energydemand organs, such as brain, heart, and skeletal muscles (Sangar et al, 2012;Watson et al, 2020). Our main interest was to identify NEM genes that are dysregulated in FRDA, which is still incurable and is challenged by the lack of treatment that can at least delay neurodegeneration despite numerous research efforts (Ocana-Santero et al, 2021). Here, we compare the transcriptomic changes between healthy controls and eight NDDs, including FRDA.…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Analysis of Nuclear-Encoded Mitochondrial Genes in Eight Neurodegenerative Disorders: The Analysis of Seven Diseases in Reference to Friedreich’s Ataxia

Elsadany¹,

Elghaish²,

Khalil³

et al. 2021

Front. Genet.

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Neurodegenerative diseases (NDDs) are challenging to understand, diagnose, and treat. Revealing the genomic and transcriptomic changes in NDDs contributes greatly to the understanding of the diseases, their causes, and development. Moreover, it enables more precise genetic diagnosis and novel drug target identification that could potentially treat the diseases or at least ease the symptoms. In this study, we analyzed the transcriptional changes of nuclear-encoded mitochondrial (NEM) genes in eight NDDs to specifically address the association of these genes with the diseases. Previous studies show strong links between defects in NEM genes and neurodegeneration, yet connecting specific genes with NDDs is not well studied. Friedreich’s ataxia (FRDA) is an NDD that cannot be treated effectively; therefore, we focused first on FRDA and compared the outcome with seven other NDDs, including Alzheimer’s disease, amyotrophic lateral sclerosis, Creutzfeldt–Jakob disease, frontotemporal dementia, Huntington’s disease, multiple sclerosis, and Parkinson’s disease. First, weighted correlation network analysis was performed on an FRDA RNA-Seq data set, focusing only on NEM genes. We then carried out differential gene expression analysis and pathway enrichment analysis to pinpoint differentially expressed genes that are potentially associated with one or more of the analyzed NDDs. Our findings propose a strong link between NEM genes and NDDs and suggest that our identified candidate genes can be potentially used as diagnostic markers and therapeutic targets.

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“…Other treatment options for Friedrich's ataxia include virus vector gene therapy, a promising area for future research. Unfortunately, this option was not available for practice at the time of this writing due to immunotoxicity and phenotoxicity [11].…”

Section: Discussionmentioning

confidence: 99%

A Case Report on Late-onset Friedrich's Ataxia and Response on Parkinsonism Treatment

Gupta

Chowdhury

2021

IJMPCR

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Friedrich's ataxia is a progressive neurodegenerative disease that affects the posterior cord of the spinal tract. We present a case of an 83-year-old male with resting tremor and rigidity that had gradually worsened over the past few years. The patient has been diagnosed with Friedrich's ataxia. Unlike typical Friedrich ataxia, this patient does not have a shortened life expectancy. There is a small percentage of atypical patients demonstrate late-onset of disease, isolated spastic paraparesis without ataxia, and retained or exacerbated deep tendon reflex. Although there is no association between Parkinson's disease and Friedrich's ataxia; in our case, treatment of tremor and rigidity improves the patient's quality of life.

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Future Prospects of Gene Therapy for Friedreich’s Ataxia

Cited by 42 publications

References 107 publications

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Mice harboring the FXN I151F pathological point mutation present decreased frataxin levels, a Friedreich ataxia-like phenotype, and mitochondrial alterations

Transcriptional Analysis of Nuclear-Encoded Mitochondrial Genes in Eight Neurodegenerative Disorders: The Analysis of Seven Diseases in Reference to Friedreich’s Ataxia

A Case Report on Late-onset Friedrich's Ataxia and Response on Parkinsonism Treatment

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