Role for HDAC3 in Friedreich’s Ataxia


Friedreich’s ataxia was first described by Nikolaus Friedreich in 1863 Image: Wikipedia
Friedreich’s ataxia was first described by Nikolaus Friedreich in 1863

Image: Wikipedia

Friedreich’s ataxia, the most common inherited ataxia, is an autosomal recessive disorder that causes progressive damage to the nervous system and heart. There are currently few treatment options and most people with the disease are ultimately confined to a wheelchair and many die as young adults.

The genetic disorder results in decreased synthesis of the protein frataxin which is essential for mitochondrial function, including oxidative phosphorylation and iron homeostasis. Reduced frataxin synthesis has been linked to abnormally expanded GAA repeats in the first intron of the frataxin gene – the length of the GAA repeats correlates with disease severity. The unusual DNA structure that results from these repetitions is believed to recruit histone deacetylases (HDACs), leading to gene silencing. In 2006, a team from the Scripps Research Institute identified N1-(2-aminophenyl)-N7-phenylheptanediamide (compound 1) as an HDAC inhibitor that reverses frataxin gene silencing in primary lymphocytes from people with Friedreich’s ataxia.

Compound 1
Later work by the group showed that a related compound, N1-(2-aminophenyl)-N7p-tolylheptanediamide (compound 2), increased frataxin production in a mouse model of Friedreich’s ataxia.
Compound 2
Although it was known that effects of the two compounds were linked to HDAC inhibition, it was not clear which particular HDAC was involved.

Working with Repligen scientists, the Scripps team have now identified HDAC3 as the key enzyme involved in Freidreich’s ataxia. Incubation of a trifunctional activity-based probe (compound 3) with a panel of class I and class II recombinant HDAC enzymes followed by addition of a fluorescent dye using click chemistry and subsequent gel electrophoresis showed that HDAC-3 was the only high affinity target for the probe.

Compound 3
Compound 3
HDAC3 was also shown to be the preferred cellular target of the probe. The team hope that a better understanding of the mechanism of action of these compounds will provide new insights into the progression of Friedreich’s ataxia and other trinucleotide repeat disorders, such as Huntington’s disease, and improve the chances of effective treatments. Compound 1 has already been shown to improve physical appearance and motor function in a mouse model of Huntington’s disease.

The study is published in the journal Chemistry & Biology.

121 thoughts on “Role for HDAC3 in Friedreich’s Ataxia”

  1. This is to the administrators of this site: Have you looked into Fulvic Acid as a treatment for FA. It has many ways to help: It has billions of electrons that it donates by electron transfer, as needed, for production of energy, and it also chelates iron from the mitochondria. Doesn’t this natural product sound like something that FA patients should be looking into, I know my daughter will.

    1. I too have a daughter with Ataxia and thought Fulvic Acid might help. I was searching to see if it had ever been used.

  2. Dr. Puccio’s team used a harmless viral vector to insert a normal copy of the problematic gene in the heart cells of FA mouse models. Since these mice show the same heart symptoms as human patients suffering from the disease the results are especially promising. The virus used was an adeno-associated virus (AAV) since it is known to effectively and efficiently target heart cells and express therapeutic diseases. This virus was modified to render it harmless and only capable of inserting the normal FXN gene copy into the cells.

    One single intravenous injection was not only able to prevent the development of heart disease in the mice, but it quickly and completely reversed the heart damage in advanced cases. Within three weeks the mice appeared to have completely restored heart and mitochondrial function and their heart tissue appeared similar to healthy mice.

    Since this is the first time that gene therapy has produced such a fast and complete remission of heart disease in an animal model work is rapidly being done to begin clinical studies. There is also hope that this technique can be used to prevent or even correct damage to the spinal cord and cerebellum.

  3. Hélène Puccio’s team tested the efficacy of this treatment in a mouse model that faithfully reproduces the heart symptoms of patients suffering from Friedreich’s ataxia. The results show that a single intravenous injection of AAVrh10 expressing frataxin is not only capable of preventing the development of heart disease in animals before the appearance of symptoms, but also, more impressively, of fully and rapidly curing the hearts of animals at an advanced stage of heart disease. After three weeks of treatment, the heart become fully functional again; mitochondrial function and the appearance of heart tissue being very similar to those of healthy mice.
    “This is the first time that gene therapy has prompted full, lasting remission of heart disease so quickly in an animal model.”

  4. Hello dears
    About HDAC inhibitor Drug Development – HDAC RG3250

    HDAC inhibitors are a class of compounds that interfere with the histone deactylase that functions to keep the DNA of a gene tightly coiled so as to silence that gene’s expression of its protein. Dr. Joel Gottesfeld of The Scripps Research Institute in La Jolla, California first described the potential use of these compounds in FA to overcome the gene silencing effect of the predominant genetic mutation that causes FA. Dr. Gottesfeld are working very closely together, with support from FARA, MDA and GoFAR, and with the FA mouse-model investigators so as to develop the very best HDAC inhibitor for FA.

    RepliGen has identified a lead candidate (RG2833). RG2833 is currently in a Phase 1 clinical trial in FA patients in Torino, Italy. This study evaluated the safety of orally dosed RG2833. RepliGen has also moved forward with identifying another HDAC inhibitor, a follow-on compound, RG3250, that they have begun pre-clinical studies in as well. RG3250 may offer some advantages over RG2833 in terms of better pharmacology, metabolic stability and brain penetration.

  5. Mona,

    The research on this site is great. Niacinamide can be purchased on Puritan’s Pride site, it’s the same as Nicotinamide, try it.

    1. hello !courtny !
      thank you my dear

      hello! courtny!thank you my dear!
      I wish health and happiness to you and your brother 21 is trying BroccoMax(Jarrow Formulas) and idebenone(smartpowders).He is in good spirits but can not stand or walk without assistance ,although we hope he get better soon . I’m hoping to treat the disease with medication, RG 2833.This is the latest news that I have read.


  6. Mona,

    That’s great news about vitamin B. I read the article about the mega doses of vitamin B, and also some further reading in a Nutritional Healing book: It says that doses of vitamin B should stay under 500 mg per day or in a few months it can result in liver problems. So, if this vitamin is safe around 400 mg per day, and it can increase a person’s existing frataxin 200% to 300%, why not give it a try now. This sounds better than garlic. Of course this is up to the individual. My daughter Courtney says she is going to try it and stay below the 500mg dose per day. Everyone do more reading for yourself. THANKS MONA FOR FINDING THIS.

    1. hello dear father!
      thank you so much!
      I hope your daughter’s health recovered quickly as possible.
      good luck

  7. Hello, I’m wondering if any of you with FA have ever tried juicing fresh wheatgrass?. I’m thinking about this for my father.

  8. Hello Dear Gary
    How is your daughter Courtney. my brother takes no garlic oil because of its odor but he takes sulforaphane and Idebenone. He can walk hardly with aid.he has good feel about the results of the first clinical phase of RG2833. I wish I could be in contact with you via email.

  9. Hello Mona, and everyone else. I am just seeing if I can get on this site, and seeing how everyone is doing. If you can get on, can you tell me how your children are doing, what they are taking, do the odorless garlic pills do more good than the regular ones. Please let me know how everyone is doing, THANK YOU.

    1. Estoy leyendo sus escritos , les enviare información sobre un producto., basado en azufre., con pruebas de regenracion impresionantes., se que les seran de utilidad ..Dios en ustedes porfa. dejenme un correo

      1. Nina,
        no se exactamente de lo què està usted hablando, pero mi correo – por si a caso quisiera enviarme algo realmente interesante sobre productos eficaces para la Friedreich , aunque lo dude – es :

  10. Hello Dear Mona,
    Very good to hear from you, I haven’t been back to check lately because I really did think they cut us off. Thanks for the Italian trials info, I will look into your info on the subject, and check back sooner, now that I know we can all get on line. Good to hear from you, how is everything with your brother.

  11. Hello dear Gary
    I hope this year will be happy year for all of us.

    New Clinical Trial in Friedreich’s Ataxia in ItalyFARA, January 5, 2012 — The Italian Health Ministry and the Ethics Committee ofthe San Luigi Hospital in Torino, Italy, have given investigators at the hospitalapproval to initiate a Phase I clinical trial of a new drug designed specifically totreat Friedreich’s ataxia. After additional study site preparations, this Phase I trialwill test the Repligen drug, known as RG2833, in patients with Friedreich’s ataxia.The investigators will aim to find out whether the drug is safe, and to learn moreabout its effects in Friedreich’s ataxia patients. In particular, they will determine ifRG2833 increases production of frataxin, a key protein that is diminished inpeople with Friedreich’s ataxia. Because lower frataxin levels are the base causeof Friedreich’s ataxia symptoms, it is hoped that, if RG2833 acts to increasefrataxin production, it could be beneficial to Friedreich’s ataxia patients.


  12. To Antonio,
    Courtney has not gotten any better, but she also has not gotten any worse, she is still walking around with her walker, and busy planning her wedding. She has started using Ubiquinol in place of CQ-10. She said it’s less pills to take, and it skips a step your body has to take to give your cells energy, she feels that Ubiquinol is as important as garlic and sulfuraphane to her well being.
    To Mona,
    That’s great news about the trials coming up, you are doing a great job keeping everyone informed about it, keep up the good work.
    To everyone,
    I certainly have missed contact with everyone, my phone line got damaged during the hurricanes, and with Verizon on strike, it has taken a while to get back on line. GOOD TO HEAR FROM EVERYONE!!!!

    1. Italian drug Authority and Turin San Luigi Hospital ethics comittee
      gave some days ago their permission to start a phase 1 trial with FA adult patients and HDAC’s Repligen Inhibitors RG2833.
      This will occur probably in Jenuary 2012 since next December 18 is scheduled the first informative meeting in Turin beetwen phisycians involved and patients/parents interested to be recruited.

    This is the last news about HDAC (or RG2833) clinical trials.

    “The European Medicines Agency (European Union’s FDA equivalent) has assented to Repligen’s proposal of a phase I clinical trial of RG2833 in FA patients. Repligen is now seeking the permission of the Italian government and the ethics committee at the Italian hospital, in Turin, where the trial is proposed. If that permission is granted, the phase I trial of RG2833 in FA patients should commence in Italy by year’s end.”

    1. Italian Drug Agency and Turin S.Luigi Hospital ethics commitee gave few days ago their permission to start with Repligen Hdac’s Inhibitors trial in FA adult patients (Phase 1 : Toxicity).
      For Sunday December 18 is scheduled first informative meeting about it (rules, elegibility criteria, timing etc….).
      I hope (think) in 2012 Jenuary will start patient recruitment.
      See you.

  14. Has someone heard something about HDAC?

    The last I heard is that they were going to start clinical trials this year.

    Cristian 30 years FA

    1. The last news about HDAC’s Inhibitors is …the same you already know : first trial will start hopefully – if FDA will take its OK – in late 2011. Also (maybe before) in Europe
      In the meanwhile , first 28 days trial with A0001, showed some neurological improvement in comparison with placebo group; in balance and walking too.
      But I’m also wondering what about Gary daughter and sulphorapano+garllic treatment.
      Has she conserved (or made better) her improvements???
      Thank you

  15. Dear Mona and Selcuk

    I hope everything is ok with Debbie and her daughter Rachael, I will also pray for them, stay in touch, good to hear from you.
    Selcuk, My daughter is still holding her own, no problems, I haven’t heard anything new that’s been approved, but I am still looking for anything that might benefit all of us. If anyone finds something new, please let all of us know. So long.

  16. Hello dear Gary
    I was waiting for Debbie responce, but unfortunately she didnt send any email for me. My prayers are with them.

  17. Hello Mona,

    That’s great news about your brother, and not getting worse is a very good thing, I know because Courtney has also not gotten any worse, she is holding her own while we all wait for something better. It’s good to hear from you Mona.
    P.S did you ever here from Debbie who has the 35 year old daughter, how is she doing. BEST REGARDS TO EVERYONE

  18. Hello everybody
    why there isnt any new comment?
    Hello Gary,How are you?How is Courtny?
    My brother has used garlic oil softgel (2 / 5000mg)and broccoli pill(2/1000mg) for 5 months.He hasnt worst.Thats a good sign.

  19. Je suis Tunisien, je porte la maladie de friedreich et je n’arrive pas à comprendre que vous venez à l’écrire en englais en ce qui conçerne la maladie si possible traduit ce que vous venez à l’écrire en français j’attends votre réponse mes remerçiments.

  20. hi all
    really im so depresed becuse we r but waiting
    every year scientists say wonderful things and we notice only that FA is in progress
    as antonio said iv ahope i still hope but my mind say scientist still far
    and id like to say that icouldn take broccoli cuz i couldnt find in syria but i take garlic and i feel im strong

  21. Gary,
    if your daughter feels good (or has unchanged, that is a big goal in FA) you’re in right giving her sulforaphane and garlic.
    But there is a lot of people that are doing the same and have not effects.
    As we have noticed with others compounds (idebenone, deferiprone, EPO, Chantix…..) sometime and for someone it can work; sometime and for other ones, it cannot work.
    Anyway, my son is still on Sulforaphane and is possibole we will add garlic).
    Nevertheless, I’m very concerned about possible effectiveness (for everybody) of these mnaturals compounds in FA, since this is a very complicated and “deep” disease that involves a lot of chemical, mechanic, electric issues in our body.
    I’m enough concerned about HDAC’s Inhibitor itself too, when it will be tested in humans (it seems impossible that just a pill could fight with a “Beast” as FA….. ).
    Don’t forget that Prof Gottesfeld (that is an extraordinary man) said in 2006 that in few (max 18) months HDAC’s Inhibitors should be tested in humans….
    But my hope is not my reason and my hope is similar to your hope.

  22. antonio,
    The mouse had lesions in the brain, it had a hump in it’s spine (much like scoliosis), it could walk only with difficulty and not very far, and Gottesfeld said it given FA to experiment with this drug. Let’s not forget, Gottesfeld first learned, a few years ago, that an HDACi they experiments on with FA blood created frataxin in 100% of the cases, we don’t know exactly what that compound is, we can only extrapolate. He did say that this is a mouse and not a human and test on humans will be the true test. That being said antonio, some one said: ” Hope is a good thing, maybe the best of things”, here, have some of mine, I have plenty to spare, you sound like you could use some. Everyone reading this that has stated above that you don’t give your children garlic should read more about it being the most powerful HDACi, plug it in google, you’ll see it. My daughter has plateaued, and I have said this a while ago, but she hasn’t gotten any worse, and she takes garlic and sulforaphane, while we wait for something better. Good luck to everyone

  23. Gary,
    unfortunately that mouse you spoke about didn’t show any (or almost any) of human Friedreich Ataxia sympthoms …..
    This is the real concern about possible efficacy in patients of that HDAC Inhibitor (actually developed by Repligen , with clinical rials continuously delayed cause FDA more pre-clinical data requests…. ) .

  24. Hello: Mona, Lolia, Paul, and Debbie. Paul your comments on 30mg BroccoMax is interesting, I will look into that. I want to tell you all about a utube site I found a 3 part conference Dr. Gottesfeld was giving in 2008 on HDACi. He called the substance he used compound 4b. I am trying to find out, through several means, what 4b is, but have been unsuccessful so far. Maybe some of you can find this site and watch it and see what you can come up with. On the 3 part utube, on the last one, he says he uses 4b, an HDACi, and it shows a mice with FA, after 11 weeks of 4b in his water, the mouse is cured. They cut open the brain and see that the lesions from FA have all but regenerated, and the mouses body, instead of being hunch backed is now lean and mean and running around like a free range mouse. I have friends looking into this formula, please someone try on your end. If it can regenerate brain tissue, Debbie, maybe it can help us all, don’t give up yet.

  25. Hi Mona, my name is Debbie i have a daghter thats 35yrs old, she has now lost her eyesited do to FA, she also is haveing hearing problems now, and shes haveing a problem standing up PLEASE write me back, I’m realy scared that i might loose her, oh! her name is Rachel and she is beautiful, and sweet, and i love her sooooooooooo much,i pray God does not want her right now, I would so appreciate if you could write me back. THANK YOU, for listening to me and God bless you and your loved ones. Debbie, my email is

  26. Interesting line of discussion. My Brianne, 33 with FA, late stage of progression, has been on BroccoMax for about 9 months and before that she was on another broccoli product that yielded only about 1mg of Sulforaphane per capsule. BroccoMax claims 30mg/capsule. During this time she has reported a better positional sense of her core, the new ability to lift her leg a little and better opening control of her fingers. She takes no garlic because it upsets her stomach, even just as a food additive.

    Another late stage FAer followed Brianne’s regimen for about 6 months with no improvement. They quit. Antonio’s comment about things working for some FAers and not others is very true. Chantix is a strong example of that.

    I believe that for almost any FA treatment the earlier it starts in a FAers progression the better. The health of the nervous system only goes down hill.

    Brianne continues to take 2 capsules a day (60mg Sulforaphane).

  27. Hello Gary ,Loila
    I saw your reply after my above reply!!!
    However, thanks.
    I have follwed the scripps research institute and professor Goel Gottesfeld works since 2009.The HDAC inhibitors 1st clinical trial , will start at 2011and we can now use Garlic and sulforophane till then fortunately.

  28. Lolia, try it and see what happens. I described above what my daughter is on. She is taking 5-250 mg pills of Broccoli sprouts, which has .21% sulforaphane each. She dropped back to one garlic pill per day, despite my insistence to the contrary, because the smell was bothering her. We are talking about her taking more Broccoli pills in the near future. When she cut down on her garlic, and she actually cut down on her sulforaphane, her feet got cold and purple again, and her joints hurt. But as I said she raised her sulforaphane back up and she is feeling better. She is still on a walker, but has stayed out of the wheel chair since she started these pills. Check out on the internet for yourself to see all the talk about sulforaphane and garlic. Use the Pubmed site, it’s very informative. Also, just plug in your questions on google. GOOD LUCK.

    The soft gel pills,for garlic, are what Courtney uses. Please seek out info on the internet about all the things that HDAC inhibitors( GARLIC AND SULFORAPHANE) are doing to treat cancer and increase frataxin in the blood, it’s amazing. GOOD LUCK.

  29. hi mona

    from my reading (i readed a lot about garlic) i found that garlic oil doesnt contain allicine so its better to take it as powder

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