Christina N Kontoghiorghe and George J Kontoghiorghes, World J Methodol. 2016 March 26; 6(1): 1–19. Published online 2016 March 26. doi: 10.5662/wjm.v6.i1.1
Open-Access
"Similar issues in relation to chelating drug development were raised with the journal Annals of Neurology regarding the use of (Ferriprox) in Friedreich ataxia patients where the lack of crucial diagnostic and therapeutic outcome procedures in relation to focal iron levels and lack of iron balance studies were questioned. The need for personalised medicine was also raised since there is wide variation in the severity of the disease and level of focal iron deposits in the heart and brain of Friedreich ataxia patients. In this case the editors of the journal referred to “expensive studies to track iron scores” and “the company developing the drug spends millions of dollars”. It should be noted that the original proposal for the use of (Ferriprox) in Friedreich ataxia patients was suggested many years ago and was developed following academic initiatives.
The introduction of Deferiprone (Ferriprox) for the treatment of non iron loaded patients by targeting focal toxic iron deposits, e.g., in Friedreich ataxia and toxic labile iron, e.g., in diabetic and non-diabetic glomerular disease is a reflection of the antioxidant and safety potential of this drug. The safety of (Ferriprox) in many categories of non iron loaded diseases has also been confirmed in clinical trials involving patients with the anaemia of chronic disease, renal dialysis, infections, Parkinson’s and other neurodegenerative diseases, etc. As in many other cases of drug development the introduction prospects of Ferriprox in these diseases is based on commercial and not ethical criteria.
Sunday, April 3, 2016
Saturday, April 2, 2016
Clinical Experience With Deferiprone Treatment for Friedreich Ataxia.
Elincx-Benizri S, Glik A, Merkel D, Arad M, Freimark D, Kozlova E, Cabantchik I, Hassin-Baer S. J Child Neurol. March 29, 2016, doi: 10.1177/0883073816636087
The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.
The authors conclude that combined therapy of a low dose of deferiprone with idebenone is relatively safe, might improve neurological function, and seems to improve heart hypertrophy, warranting further studies.
Friday, April 1, 2016
Assessment and management of cavus foot deformity
J. Grice, H. Willmott, H. Taylor, Orthopaedics and Trauma, Available online 8 March 2016, ISSN 1877-1327, doi:10.1016/j.mporth.2016.02.001.
Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot.
Careful examination should be performed and underlying neurological conditions sought. We outline an á la carte approach to surgical management, in which deformity of the ankle and hindfoot is addressed before moving on to assessment and correction of the mid- and forefoot.
Thursday, March 31, 2016
Iron Homeostasis in Health and Disease
Raffaella Gozzelino, and Paolo Arosio; Review: Int. J. Mol. Sci. 2016, 17(1), 130; doi:10.3390/ijms17010130
OPEN ACESS
It is established the involvement of this metal in Friedrich’s ataxia, a disease characterized by progressive degeneration of sensory neurons in the dorsal root ganglia caused by a mutation in the frataxin gene. Frataxin plays an essential role in delivering Fe to mitochondrial pathways involved in ISC biogenesis and when its functionality is reduced below a critical threshold, Fe accumulates in mitochondria. Reduced mitochondrial functioning and impaired electron transport chain results in Fe-mediated ROS, which was shown to positively correlate with the severity of Friedrich’s ataxia.
OPEN ACESS
It is established the involvement of this metal in Friedrich’s ataxia, a disease characterized by progressive degeneration of sensory neurons in the dorsal root ganglia caused by a mutation in the frataxin gene. Frataxin plays an essential role in delivering Fe to mitochondrial pathways involved in ISC biogenesis and when its functionality is reduced below a critical threshold, Fe accumulates in mitochondria. Reduced mitochondrial functioning and impaired electron transport chain results in Fe-mediated ROS, which was shown to positively correlate with the severity of Friedrich’s ataxia.
Wednesday, March 30, 2016
Genome Editing of Structural Variations: Modeling and Gene Correction
Chul-Yong Park, Jin Jea Sung, Dong-Wook Kim, Trends in Biotechnology, Available online 23 March 2016, ISSN 0167-7799, doi:10.1016/j.tibtech.2016.02.011.
Although in vivo gene correction using genetic scissor technology (Meganucleases, ZFNs, TALENs and CRISPR/Cas9) may be available and desirable in the future, effective and cell-specific delivery systems should be developed. These technologies promise to expand our understanding of the mechanism of SVs and our ability to treat SV-related diseases.
For Friedreich's ataxia (FRDA), regions containing GAA repeats from frataxin(FXN) intron 1 were removed by expressing ZFNs targeting 334bp and 896bp upstream of GAA repeats in FRDA fibroblasts and lymphoblasts. The FRDA phenotype was reversed, with increased frataxin expression, when corrected FRDA fibroblasts were converted to iPSCs and differentiated into neurons (Li, Y. et al. (2015)).
Although in vivo gene correction using genetic scissor technology (Meganucleases, ZFNs, TALENs and CRISPR/Cas9) may be available and desirable in the future, effective and cell-specific delivery systems should be developed. These technologies promise to expand our understanding of the mechanism of SVs and our ability to treat SV-related diseases.
For Friedreich's ataxia (FRDA), regions containing GAA repeats from frataxin(FXN) intron 1 were removed by expressing ZFNs targeting 334bp and 896bp upstream of GAA repeats in FRDA fibroblasts and lymphoblasts. The FRDA phenotype was reversed, with increased frataxin expression, when corrected FRDA fibroblasts were converted to iPSCs and differentiated into neurons (Li, Y. et al. (2015)).
Tuesday, March 29, 2016
Translatability: What does it mean in drug discovery?
Matthew Tudor, Jeffery Hermes, Jing Li (Screening & Protein Science, Merck Research Laboratories,USA), Drug Discovery Today, Available online 26 March 2016, ISSN 1359-6446, doi:10.1016/j.drudis.2016.03.010.
We can develop multiple disease-relevant in vitro and in vivo models as a means of further validation of the initial target hypothesis, and pursue decisive experiments that will enable early no-go calls to be made on targets. However, such surrogate assays can reach the wrong conclusion because they will have imperfect predictivity of the results of a well-designed Phase II clinical trial. Disease relevant assays can serve as ‘gate-keepers’ to inform the probability of the translatability but always have to be interpreted as suggestive rather than definitive.
Friedreich’s ataxia (FA), an autosomal-recessive disease, is caused by a trinucleotide GAA repeat expansion which leads to the reduction of FXN protein expression. The protein function is not entirely understood. Attempts to correct putative FXN mutation sequelae by reversing mitochondrial dysfunction, such as by using ion chelators and antioxidants, are broadly reported. Such symptomatic intervention can be viewed as spreading of bets in addition to direct FXN protein intervention, but the odds are clearly against such nonspecific approaches because of the unknown FXN biology. The more certain bet is on what human genetics is telling us: that restoration of FXN protein levels would be effective. To that end, efforts to improve the rate of transcriptional read-through or splicing would be expected to have higher chances of significantly impacting the clinical state.
We can develop multiple disease-relevant in vitro and in vivo models as a means of further validation of the initial target hypothesis, and pursue decisive experiments that will enable early no-go calls to be made on targets. However, such surrogate assays can reach the wrong conclusion because they will have imperfect predictivity of the results of a well-designed Phase II clinical trial. Disease relevant assays can serve as ‘gate-keepers’ to inform the probability of the translatability but always have to be interpreted as suggestive rather than definitive.
Friedreich’s ataxia (FA), an autosomal-recessive disease, is caused by a trinucleotide GAA repeat expansion which leads to the reduction of FXN protein expression. The protein function is not entirely understood. Attempts to correct putative FXN mutation sequelae by reversing mitochondrial dysfunction, such as by using ion chelators and antioxidants, are broadly reported. Such symptomatic intervention can be viewed as spreading of bets in addition to direct FXN protein intervention, but the odds are clearly against such nonspecific approaches because of the unknown FXN biology. The more certain bet is on what human genetics is telling us: that restoration of FXN protein levels would be effective. To that end, efforts to improve the rate of transcriptional read-through or splicing would be expected to have higher chances of significantly impacting the clinical state.
Monday, March 28, 2016
Mitochondrial iron overload: causes and consequences
Tracey A Rouault, Current Opinion in Genetics & Development, Volume 38, June 2016, Pages 31-37, ISSN 0959-437X, http://dx.doi.org/10.1016/j.gde.2016.02.004.
The mystery of mitochondrial iron overload diseases — how is mitochondrial iron homeostasis regulated? Despite the fact that much is now known about how mitochondrial Fe-S clusters are assembled and transferred, several major mysteries remain about how mitochondria regulate iron homeostasis in the mitochondrial matrix.The challenge ahead is to identify the full roster of transporters involved in mitochondrial iron homeostasis and to try to identify a regulatory ‘overlord’ that regulates a nuclear transcriptional response to perceived iron deficiency.
The mystery of mitochondrial iron overload diseases — how is mitochondrial iron homeostasis regulated? Despite the fact that much is now known about how mitochondrial Fe-S clusters are assembled and transferred, several major mysteries remain about how mitochondria regulate iron homeostasis in the mitochondrial matrix.The challenge ahead is to identify the full roster of transporters involved in mitochondrial iron homeostasis and to try to identify a regulatory ‘overlord’ that regulates a nuclear transcriptional response to perceived iron deficiency.
Sunday, March 27, 2016
Using human pluripotent stem cells to study Friedreich ataxia cardiomyopathy
Duncan E. Crombie, Martin F. Pera, Martin B. Delatycki, Alice Pébay, International Journal of Cardiology, Available online 21 March 2016, ISSN 0167-5273, doi:10.1016/j.ijcard.2016.03.040.
Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease mode.
Here, we summarise current knowledge on experimental models in which to study FRDA cardiomyopathy, with a particular focus on the use of human pluripotent stem cells as a disease mode.
Saturday, March 26, 2016
Gastrocnemius and soleus spasticity and muscle length in Friedreich’s ataxia
Sarah C. Milne, Louise A. Corben, Eppie Yiu, Martin B. Delatycki, Nellie Georgiou-Karistianis, Journal of Clinical Neuroscience, Available online 25 March 2016, ISSN 0967-5868, doi:10.1016/j.jocn.2016.01.011.
Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.
Gastrocnemius and soleus spasticity and contracture is apparent in people with FRDA. Spasticity is evident early in the disease and in ambulant participants. Management of spasticity and reduced muscle length should be considered in people with FRDA at disease onset to optimise function.
Friday, March 25, 2016
Letter: Tissue atrophy and elevated iron concentration in the extrapyramidal motor system in Friedreich ataxia: the IMAGE-FRDA study
Ian H Harding, Parnesh Raniga, Martin B Delatycki, Monique R Stagnitti, Louise A Corben, Elsdon Storey, Nellie Georgiou-Karistianis, Gary F Egan. J Neurol Neurosurg Psychiatry doi:10.1136/jnnp-2015-312665 Published Online First: 24 March 2016
In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.1–3 The dentate nuclei are iron-laden structures pivotal to movement coordination. However, basal ganglia and midbrain structures also have high iron content, express high levels of frataxin, and play key roles in motor regulation. Furthermore, the dentate nuclei directly innervate the thalamus and red nuclei, and indirectly project to the striatum. This biology motivates the hypothesis that iron-related pathology and/or degeneration within these extrapyramidal stations may also feature in FRDA.
In the brain, accumulation or redistribution of iron within, and atrophy of, the cerebellar dentate nuclei have been reported.1–3 The dentate nuclei are iron-laden structures pivotal to movement coordination. However, basal ganglia and midbrain structures also have high iron content, express high levels of frataxin, and play key roles in motor regulation. Furthermore, the dentate nuclei directly innervate the thalamus and red nuclei, and indirectly project to the striatum. This biology motivates the hypothesis that iron-related pathology and/or degeneration within these extrapyramidal stations may also feature in FRDA.
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