Yannis Dionyssiotis, Athina Kapsokoulou, Anna Danopoulou, Maria Kokolaki & Athina Vadalouka; Spinal Cord Series and Casesvolume 4, Article number: 38 (2018) doi:10.1038/s41394-018-0071-x
We present two cases, a brother (54 years old) and sister (56 years old), with FDRA that are chronically institutionalized for incomplete quadriplegia without spasticity. Gait and postural ataxia, cerebellar dysarthria, oculomotor dysfunction, musculoskeletal deformities, hearing impairment, hypertrophic cardiomyopathy, and diabetes mellitus are also present. Neurological examination reveals extensor plantar responses and diminished to absent tendon reflexes. Both are wheelchair bound, cannot perform daily tasks and need assistance.
Although there is no cure that can alter the natural course of the disease physiotherapy, management of spasticity and neuropathic pain, symptomatic treatment of heart failure and diabetes and nursing care can grant the patients quality of life.
Saturday, April 28, 2018
Increased frataxin expression induced in Friedreich ataxia cells by platinum TALE-VP64s or platinum TALE-SunTag
Khadija Cherif, Catherine Gérard, Joël Rousseau, Dominique L. Ouellet, Pierre Chapdelaine, Jacques P. Tremblay, Molecular Therapy - Nucleic Acids, Available online 27 April 2018, ISSN 2162-2531, doi:10.1016/j.omtn.2018.04.009
Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria’s iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA), such as VP64 or P300, were used to increase the expression of that gene. Many effectors plTALEVP64, plTALEp300 and plTALESunTag targeting 14 sequences of the FXN gene promoter or intron 1 were produced. This permitted to select 3 plTALEVP64s and 2 plTALESunTag that increased FXN gene expression by up to 19 folds in different FRDA primary fibroblasts. Adeno-Associated Viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected plTALEVP64s or plTALESunTag induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10 folds and in skeletal muscles by up to 35 folds. The aconitase activity is positively modulated by the frataxin level in mitochondria and was thus increased in vitro and in vivo by the increased frataxin expression.
Frataxin gene (FXN) expression is reduced in Friedreich's ataxia patients due to an increase in the number of GAA trinucleotides in intron 1. The frataxin protein, encoded by that gene, plays an important role in mitochondria’s iron metabolism. Platinum TALE (plTALE) proteins targeting the regulatory region of the FXN gene, fused with a transcriptional activator (TA), such as VP64 or P300, were used to increase the expression of that gene. Many effectors plTALEVP64, plTALEp300 and plTALESunTag targeting 14 sequences of the FXN gene promoter or intron 1 were produced. This permitted to select 3 plTALEVP64s and 2 plTALESunTag that increased FXN gene expression by up to 19 folds in different FRDA primary fibroblasts. Adeno-Associated Viruses were used to deliver the best effectors to the YG8R mouse model to validate their efficiencies in vivo. Our results showed that these selected plTALEVP64s or plTALESunTag induced transcriptional activity of the endogenous FXN gene as well as expression of the frataxin protein in YG8R mouse heart by 10 folds and in skeletal muscles by up to 35 folds. The aconitase activity is positively modulated by the frataxin level in mitochondria and was thus increased in vitro and in vivo by the increased frataxin expression.
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