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Positive effects of fractin level restoration is signs of decrease in progression of FRDA. Therapeutic use of HDACI led to the normalization of the genetic expression of FRDA patients. Support of fractin level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to histones without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.
 
Positive effects of fractin level restoration is signs of decrease in progression of FRDA. Therapeutic use of HDACI led to the normalization of the genetic expression of FRDA patients. Support of fractin level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to histones without producing any toxic effects upon the brain where no pathological effects from FRDA where identified<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.
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Revision as of 19:39, 4 October 2011

Alternate treatment

Iron chelations

Iron chelations potential as treatment for FA is greatly focused. Regarding pathogenesis of FA is due to he mitochondrial accumulation of Iron, causing a usage of cytosolic iron[1].Where most potential chelators are those which specifically target mitochondrial pools of iron[2].There is evidence that due to the fractin deficiency results in FA caused from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal[3].


Articles to read:

"""Carido"""


[4]

Treatment

Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay [5] FRDA. Main cause for the congenital disorder is the mitochondrial gene dysfunction where Frataxin levels are below normal range causing cascade of effects: increase Mitochondrial Iron - Sulfur clusters and Mitochondrial Damage[6]. However there are various potential treatments which have shown signs of improvement from FRDA patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant. Each treatment targeting a particular abnomality and are the leading treatments for FRDA[7][8][9].


Iron-chelation

Iron chelations potential as treatment for Friedrichs Ataxia (FRDA) is greatly focused, within areas regarding to pathogenesis. FRDA effects the Mitochondria leading to Mitochondrial accumulation of Iron causing a usage of cytosolic iron[1].There is evidence that due to the Frataxin deficiency in FRDA patients results in the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range[3] to counter the rate of depletion.Where most potential chelators are those which specifically target mitochondrial pools of iron[2] for the reason of maintenance of Iron within cystol of the cell.

As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron- chelation had been studied for it's therapeutic action on removing excess iron in mouse models. Between treated mice and untreated mice, the treated mice showed a decrease in heart weight and heart to body ratio. This demonstrates that while chelation limits cardiomyopathy, it did not 'cure' the problem. As chelation did not lead to major iron depletion or toxicity reduction, and prevented iron accumulation in mice with the mutated frataxin gene it has opened up a possible treatment path of preventing mitochondrial iron build up - stopping the production of toxic agents and free radicals before they can be produced. Additionally, mice treated with chelation did not show any changes in the histology of the heart or any other major organ. It also did not lead to red blood cell loss, decreased hemoglobin concentration or hematocrit[10].


Histone deacetylase inhibitors(HDACI)


Treatment of FRDA through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes[11]. HDACI has shown signs of increasing levels of fractin restoring to normal range within the nervous system and the heart, restoration of fractin levels was achieved where acetylisation of histones at the GAA repeat in FRDA patients in both the heart and central nervous system[12].

Positive effects of fractin level restoration is signs of decrease in progression of FRDA. Therapeutic use of HDACI led to the normalization of the genetic expression of FRDA patients. Support of fractin level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to histones without producing any toxic effects upon the brain where no pathological effects from FRDA where identified[13].


Antioxidants

The most promising antioxidant treatments are Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria, however there are still ongoing trials to show its effectiveness.

  • Conenzyme Q10 is an electron carrier with a reduction of oxidative stress effect from the combination of vitamin E, combination of Q10 and vitamin E displayed a positive effect[14]. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement, mitochondrial ATP synthesis is effected with reduction of oxidative damage allowing better function delaying effect of FRDA[15].
  • Idebnone operates with a duel function in which it reverses redox reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage[8]. Usage of Idebenone has been proven to reduce cardiac hypertrophy in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial[16], though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy[17]. Thus Idebenone is frequently used a treatment method although other alternatives are present including erythropoietin and other gene-based strategies[18].

genetic treatment

alternate treatment of FRDA is through histone deacetylase inhibitor (HDACI) which has shown potential as treatment in reversing heterochromatin of genes[11]. HDACI has shown sign of increasing levels of fractin to normal range within the nervous system and the heart, positive effects of fractin levels has given signs of decrease in progression of FRDA. Therapeutic use of HDACI led to the normalization of the genetic expression of FRDA patients from the minute levels of fractin. Clearly from mouse models depict therapeutic effect of HDACI, HDACI is able to cross through the blood brain barrier elevating levels of histone acetylation without having toxic effects upon the brain though has shown no affiliation to fractin levels instead affecting GAA repeat[13].

Treatment of FRDA through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes[11]. HDACI has shown signs of increasing levels of fractin restoring to normal range within the nervous system and the heart, restoration of fractin levels was achieved where acetylisation of histones at the GAA repeat in FRDA patients in both the heart and central nervous system[12].

Positive effects of fractin level restoration is signs of decrease in progression of FRDA. Therapeutic use of HDACI led to the normalization of the genetic expression of FRDA patients. Support of fractin level restoration is clearly identified from the KIKI mouse models depict therapeutic effect of HDACI displaying no signs of pathologyical or abnormal behaviour, while HDACI is able to cross the blood brain barrier and procede with aceytlsation to histones without producing any toxic effects upon the brain where no pathological effects from FRDA where identified[13].


Role of FXN Gene
  1. 1.0 1.1 <pubmed>10805340</pubmed>
  2. 2.0 2.1 <pubmed>20156111</pubmed>
  3. 3.0 3.1 <pubmed>18424449</pubmed>
  4. <pubmed>19283344</pubmed>
  5. <pubmed>19283349</pubmed>
  6. <pubmed>19305405</pubmed>
  7. <pubmed>19283350</pubmed>
  8. 8.0 8.1 <pubmed>19283347</pubmed>
  9. <pubmed>17968974</pubmed>
  10. <pubmed>18621680</pubmed>
  11. 11.0 11.1 11.2 <pubmed>16205715</pubmed>
  12. 12.0 12.1 <pubmed>16921367</pubmed>
  13. 13.0 13.1 13.2 <pubmed>18463734</pubmed>
  14. <pubmed>19049556</pubmed>
  15. <pubmed>15824263</pubmed>
  16. <pubmed>11907009</pubmed>
  17. <pubmed>19363628</pubmed>
  18. <pubmed>20856912</pubmed>