User talk:Z3332250: Difference between revisions

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Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref>. However there are various potential treatments which have shown signs of improvement from FRDA, antioxidant and Iron chelation are the leading treatments towards FRDA<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.
Currently For the degenerative congenital disorder Friedreichs Ataxia (FRDA) this is no current treatment to reverse, prevent and delay <ref name="PMID:19283349"><pubmed>19283349</pubmed></ref> [[#Glossary | '''FRDA''']]. However there are various potential treatments which have shown signs of improvement from FRDA patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant are the leading treatments towards [[#Glossary | '''FRDA''']]<ref name="PMID:19283350"><pubmed>19283350</pubmed></ref><ref name="PMID:19283347"><pubmed>19283347</pubmed></ref><ref name="PMID:17968974"><pubmed>17968974</pubmed></ref>.




friedreich Ataxia (FA) a progressive neurological congenital disorder<ref name="PMID19283349"><pubmed>19283349</pubmed></ref>, wtih no treatment identified only possible pharmaceutics which can reduce the progression of FA however not significantly. Whereas significant treatment poties  of FA or reduction in progression are the following:
'''Iron-chelation'''


*Iron-chelation
Iron [[#Glossary | '''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<ref name="PMID:10805340"><pubmed>10805340</pubmed></ref>.There is evidence that due to the [[#Glossary | '''Frataxin''']] deficiency resulted in FRDA patients is from the depletion of cytosolic iron, it has been suggested therapeutic treatment of iron supplements to replenish cytosolic iron to normal range<ref name="PMID:18424449"><pubmed>18424449</pubmed></ref> to counter the rate of depletion.Where most potential [[#Glossary | '''chelators''']] are those which specifically target mitochondrial pools of iron<ref name="PMID:20156111"><pubmed>20156111</pubmed></ref> for the reason of maintenance of Iron within cystol of the cell.
**deferoxamine
*Antioxidants:
**Idebenone
**Coenzyme Q10 and Vitamin E


Antioxidants treatment of FA which have shown most promise is Idebenone and Coenzyme Q10 with Vitamin E. Antioxidants have shown degree of reduction on oxidative stress in mitochondria though are still going through clinical trials<ref name="PMID:19283349">19283349</pubmed></ref>.Conenzyme Q10 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<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement with the betterment of the mitochondrial synthesis<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.
As cardiomyopathy is believed to be caused by the production of toxic agents from the excess iron reacting within mitochondria, Iron-[[#Glossary | '''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 [[#Glossary | '''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 [[#Glossary | '''hematocrit''']]<ref name="PMID:18621680"><pubmed>18621680</pubmed></ref>.


Idebnone operates with a duel function where reversing redox reactions affecting electron balance in the mitochondria while also supporting mitochondria functions preventing damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>.


----
'''Histone deacetylase inhibitors(HDACI)'''
 
Treatment of [[#Glossary | '''FRDA''']] through [[#Glossary | '''histone deacetylase inhibitor''']] (HDACI) has shown potential as treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown sign of increasing levels of [[#Glossary | '''Frataxin''']] to normal range within the nervous system and the heart, positive effects of [[#Glossary | '''Frataxin''']] levels has given signs of decrease in progression of [[#Glossary | '''FRDA''']]. Therapeutic use of HDACI led to the normalization of the genetic expression of [[#Glossary | '''FRDA''']] patients from the minute levels of [[#Glossary | '''Frataxin''']]. 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 [[#Glossary | '''Frataxin''']] levels instead affecting GAA repeat<ref name="PMID:18463734"><pubmed>18463734</pubmed></ref>.
 
 
Treatment of [[#Glossary | '''FRDA''']] through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes<ref name="PMID:16205715"><pubmed>16205715</pubmed></ref>. HDACI has shown signs of increasing levels of [[#Glossary | '''fractin''']] restoring to normal range within the nervous system and the heart, restoration of [[#Glossary | '''fractin''']] levels was achieved where acetylisation of [[#Glossary | '''histones''']] at the GAA repeat in FRDA patients in both the heart and central nervous system<ref name="PMID:16921367"><pubmed>16921367</pubmed></ref>.
 
Positive effects of [[#Glossary | '''fractin''']] level restoration is signs of decrease in progression of [[#Glossary | '''FRDA''']]. Therapeutic use of HDACI led to the normalization of the genetic expression of [[#Glossary | '''FRDA''']] patients. Support of [[#Glossary | '''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 [[#Glossary | '''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>.
 
 
'''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<ref name="PMID:19049556"><pubmed>19049556</pubmed></ref>. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement with the betterment of the mitochondrial synthesis<ref name="PMID:15824263"><pubmed>15824263</pubmed></ref>.


*Idebnone operates with a duel function in which it reverses [[#Glossary | '''redox''']] reactions that affects electron balance in the mitochondria while also supporting mitochondria functions to prevent damage<ref name="PMID:19283347"><pubmed>19283347</pubmed></ref>. Usage of Idebenone has been proven to reduce cardiac [[#Glossary | '''hypertrophy''']] in FRDA indicating a 20% reduction on left ventricular mass from cardiac ultrasound in half the patients during trial<ref name="PMID:11907009"><pubmed>11907009</pubmed></ref>, though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy<ref name="PMID:19363628"><pubmed>19363628</pubmed></ref>. Thus Idebenone is frequently used a treatment method although other alternatives are present including [[#Glossary | '''erythropoietin''']] and other gene-based strategies<ref name="PMID:20856912"><pubmed>20856912</pubmed></ref>.


----


=genetic treatment=
=genetic treatment=

Revision as of 12:47, 1 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. However there are various potential treatments which have shown signs of improvement from FRDA patients include, Iron chelation, Histone deacetylase inhibitors(HDACI) and antioxidant are the leading treatments towards FRDA[6][7][8].


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 resulted in FRDA patients is from 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[9].


Histone deacetylase inhibitors(HDACI)

Treatment of FRDA through histone deacetylase inhibitor (HDACI) has shown potential as treatment in reversing heterochromatin of genes[10]. HDACI has shown sign of increasing levels of Frataxin to normal range within the nervous system and the heart, positive effects of Frataxin 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 Frataxin. 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 Frataxin levels instead affecting GAA repeat[11].


Treatment of FRDA through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes[10]. 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[11].


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[13]. Where Q10 and vitamin E conveyed the cardiac and skeletal improvement with the betterment of the mitochondrial synthesis[14].
  • 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[7]. 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[15], though the dosage of Idebenone give is at low dosage treatments of 5mg/kg/day which has shown reduction in cardiac hypertrophy[16]. Thus Idebenone is frequently used a treatment method although other alternatives are present including erythropoietin and other gene-based strategies[17].

genetic treatment

alternate treatment of FRDA is through histone deacetylase inhibitor (HDACI) which has shown potential as treatment in reversing heterochromatin of genes[10]. 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[11].

Treatment of FRDA through histone deacetylase inhibitor (HDACI) has shown potential as a treatment in reversing heterochromatin of genes[10]. 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[11].

  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>19283350</pubmed>
  7. ↑ 7.0 7.1 <pubmed>19283347</pubmed>
  8. ↑ <pubmed>17968974</pubmed>
  9. ↑ <pubmed>18621680</pubmed>
  10. ↑ 10.0 10.1 10.2 10.3 <pubmed>16205715</pubmed>
  11. ↑ 11.0 11.1 11.2 11.3 <pubmed>18463734</pubmed>
  12. ↑ 12.0 12.1 <pubmed>16921367</pubmed>
  13. ↑ <pubmed>19049556</pubmed>
  14. ↑ <pubmed>15824263</pubmed>
  15. ↑ <pubmed>11907009</pubmed>
  16. ↑ <pubmed>19363628</pubmed>
  17. ↑ <pubmed>20856912</pubmed>
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