scholarly journals Future Prospects of Gene Therapy for Friedreich’s Ataxia

2021 ◽  
Vol 22 (4) ◽  
pp. 1815 ◽  
Author(s):  
Gabriel Ocana-Santero ◽  
Javier Díaz-Nido ◽  
Saúl Herranz-Martín
Keyword(s):  
Gene Therapy ◽  
Viral Vectors ◽  
Autosomal Recessive ◽  
State Of The Art ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
First Intron ◽  
Progressive Neurodegeneration ◽  
Feasible Solutions ◽  
Neurogenetic Disease

Friedreich’s ataxia is an autosomal recessive neurogenetic disease that is mainly associated with atrophy of the spinal cord and progressive neurodegeneration in the cerebellum. The disease is caused by a GAA-expansion in the first intron of the frataxin gene leading to a decreased level of frataxin protein, which results in mitochondrial dysfunction. Currently, there is no effective treatment to delay neurodegeneration in Friedreich’s ataxia. A plausible therapeutic approach is gene therapy. Indeed, Friedreich’s ataxia mouse models have been treated with viral vectors en-coding for either FXN or neurotrophins, such as brain-derived neurotrophic factor showing promising results. Thus, gene therapy is increasingly consolidating as one of the most promising therapies. However, several hurdles have to be overcome, including immunotoxicity and pheno-toxicity. We review the state of the art of gene therapy in Friedreich’s ataxia, addressing the main challenges and the most feasible solutions for them.

scholarly journals Epigenetics in Friedreich's Ataxia: Challenges and Opportunities for Therapy

2013 ◽  
Vol 2013 ◽  
pp. 1-12 ◽  
Author(s):  
Chiranjeevi Sandi ◽  
Sahar Al-Mahdawi ◽  
Mark A. Pook
Keyword(s):  
Autosomal Recessive ◽  
Trinucleotide Repeat ◽  
Neurodegenerative Disorder ◽  
Therapeutic Option ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Epigenetic Changes ◽  
First Intron ◽  
Challenges And Opportunities ◽  
Transcriptional Reactivation

Friedreich's ataxia (FRDA) is an autosomal recessive neurodegenerative disorder caused by homozygous expansion of a GAA·TTC trinucleotide repeat within the first intron of the FXN gene, leading to reduced FXN transcription and decreased levels of frataxin protein. Recent advances in FRDA research have revealed the presence of several epigenetic modifications that are either directly or indirectly involved in this FXN gene silencing. Although epigenetic marks may be inherited from one generation to the next, modifications of DNA and histones can be reversed, indicating that they are suitable targets for epigenetic-based therapy. Unlike other trinucleotide repeat disorders, such as Huntington disease, the large expansions of GAA·TTC repeats in FRDA do not produce a change in the frataxin amino acid sequence, but they produce reduced levels of normal frataxin. Therefore, transcriptional reactivation of the FXN gene provides a good therapeutic option. The present paper will initially focus on the epigenetic changes seen in FRDA patients and their role in the silencing of FXN gene and will be concluded by considering the potential epigenetic therapies.

Stress-Induced Mouse Model of the Cardiac Manifestations of Friedreich's Ataxia Corrected by AAV-mediated Gene Therapy

2020 ◽  
Vol 31 (15-16) ◽  
pp. 819-827 ◽  
Author(s):  
Christiana O. Salami ◽  
Katie Jackson ◽  
Clarisse Jose ◽  
Laith Alyass ◽  
Georges-Ibrahim Cisse ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Cardiac Manifestations

scholarly journals Amino Acid Changes in the Mouse Mutant Dystonia Musculorum Similar to Those in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 185-188 ◽  
Author(s):  
A. Messer
Keyword(s):  
Amino Acid ◽  
Experimental Model ◽  
Neurological Disorder ◽  
Autosomal Recessive ◽  
Red Nucleus ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Mouse Mutant ◽  
Sensory Afferents ◽  
Recessive Mutant

SUMMARY:An autosomal recessive mutant strain of mouse with a progressive neurological disorder is described. Histopathology is dramatic in the sensory afferents and in the red nucleus. In the cerebellar vermis the concentrations of glutamate, aspartate, glycine and GABA are significantly reduced, and in the cerebellar hemispheres the taurine/glutamate ratio is elevated. These mice may provide a useful experimental model of Friedreich’s ataxia.

scholarly journals Electromyography and Nerve Conduction Studies in Friedreich's Ataxia and Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS)

1979 ◽  
Vol 6 (2) ◽  
pp. 185-189 ◽  
Author(s):  
J.P. Bouchard ◽  
A. Barbeau ◽  
R. Bouchard ◽  
R.W. Bouchard
Keyword(s):  
Nerve Conduction ◽  
Autosomal Recessive ◽  
Clinical Signs ◽  
Sensory Nerve ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Nerve Conduction Studies ◽  
Spastic Ataxia ◽  
Group I ◽  
Electrophysiological Studies

SummaryTwenty four ataxie patients were investigated with electromyography and nerve conduction studies. They were divided in two groups according to the area they came from, the evolution of the disease, and the clinical signs. Group I patients from the Rimouski area displayed all the clinical and electrophysiological signs of Friedreich's ataxia. Group II comprised patients who presented with a new syndrome known as the autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Although the clinical evolution was better in the latter, there were more electromyographic signs of denervation and the motor conduction velocities were slower. Both groups showed identical and important abnormalities in sensory nerve conduction.The results of electrophysiological studies in spastic ataxia have not been reported to our knowledge. They underline the place of spastic ataxia as distinct f rom Friedreich's ataxia, spastic paraplegia, and the known familial neuropathies.

scholarly journals A Possible Genetic Pattern of Taurine Urinary Excretion in Friedreich’s Ataxia

1982 ◽  
Vol 9 (2) ◽  
pp. 209-215 ◽  
Author(s):  
A. Barbeau ◽  
F. Patenaude ◽  
G. Nadon ◽  
M. Charbonneau ◽  
T. Cloutier
Keyword(s):  
Urinary Excretion ◽  
Autosomal Recessive ◽  
Genetic Defect ◽  
High Capacity ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Uptake System ◽  
Genetic Pattern ◽  
Before And After ◽  
Normal Controls

SUMMARY:The taurine urinary excretion pattern, before and after an oral load of 250 mg taurine, was studied in normal control subjects and in patients with typical Friedreich’s ataxia. It was demonstrated that in both situations the ataxic patients fell within the sub-types of “intermediate” and “high taurine excretors”, while none were “low taurine excretors”. It was also demonstrated that the excretion of taurine after a load in the obligate heterozygotes parents of the ataxic patients was intermediate between normal controls and patients. It is postulated that patients with Friedreich’s Ataxia lack normal regulation of the high affinity-low capacity uptake system for taurine (the TH system) in the brush border of kidney tubules. The low affinity-high capacity uptake system in the same membranes (the TL system) appears to be normal in Friedreich’s patients. The normal allele could be called THN and the variant THF and this trait would be inherited in an autosomal recessive fashion if it is linked to the Freidreich phenotype. Whether this finding is or is not the basic genetic defect in Friedreich’s Ataxia will require more studies to clarify, but it is of interest to note that a similar pattern appears to be present in the fibroblasts of these patients.

scholarly journals Computed Tomography of Posterior Fossa in Hereditary Ataxias

1979 ◽  
Vol 6 (2) ◽  
pp. 195-198 ◽  
Author(s):  
R. Langelier ◽  
J.P. Bouchard ◽  
R.B Ouchard
Keyword(s):  
Computed Tomography ◽  
Central Nervous System ◽  
Nervous System ◽  
Posterior Fossa ◽  
Autosomal Recessive ◽  
Cerebellar Atrophy ◽  
Friedreich’S Ataxia ◽  
Friedreich's Ataxia ◽  
Hereditary Ataxias ◽  
The Central Nervous System

SummaryNine cases of Friedreich's ataxia and seven cases of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) were submitted to neuroradiological procedures to determine the extent of atrophie processes in the central nervous system. All cases had a computerized cerebral tomography and five were studied with pneumencephalo-graphy. The results show a correlation between the two tests and the comparison between Friedreich's ataxia and ARS ACS.In Friedreich's ataxia, the radiological signs are variable and discrete in most of the cases. In A RSA CS there are constant signs of cerebellar atrophy almost limited to the superior parts of the vermis and anterior lobes.

scholarly journals Next-Generation Gene Therapy for Parkinson’s Disease Using Engineered Viral Vectors

2021 ◽  
pp. 1-9
Author(s):  
Tomas Björklund ◽  
Marcus Davidsson
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Clinical Trials ◽  
Genome Editing ◽  
Viral Vectors ◽  
State Of The Art ◽  
The State ◽  
Next Generation ◽  
Suitable Vector

Recent technological and conceptual advances have resulted in a plethora of exciting novel engineered adeno associated viral (AAV) vector variants. They all have unique characteristics and abilities. This review summarizes the development and their potential in treating Parkinson’s disease (PD). Clinical trials in PD have shown over the last decade that AAV is a safe and suitable vector for gene therapy but that it also is a vehicle that can benefit significantly from improvement in specificity and potency. This review provides a concise collection of the state-of-the-art for synthetic capsids and their utility in PD. We also summarize what therapeutical strategies may become feasible with novel engineered vectors, including genome editing and neuronal rejuvenation.

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