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. HELLO, Gary
    We use garlic oil (with oddor) soft gel. Has it the same effect(pill)?
    Do you have any good news?
    Thanks a lot

  2. Hi
    My sister and I have FA and we want to try broccoli and garlic but we dont know how to take it?
    Since broccoli contains 2,5% sulforaphane it means a pill with 1000 mg broccoli = 25 mg sulforaphane??????????????
    Is 2000 mg broccoli enough?
    ur daughter took garlic with smell??????????????

  3. Hi Maja.
    We didn’t notice improvements so last week we have increased Sulforaphane up to 30 mg daily.
    Hope it could work better.
    But every FAer is so different……

  4. TO: Brenda, Mona, Maja , and everyone interested: Courtney is doing ok. She has moved out of the house and living with her fiancee, she just went through testing from DMV , and has a hand control on her car and is getting ready for driving classes. She is still using her walker and gets around very well. She cooks their meals, cleans house, etc. Courtney is usually in a very good mood because she feels she was heading in a different direction than she is now: she was in her wheel chair, blue & cold feet, not being able to tell where her feet where when she walked or to feel much of anything with her feet, and her balance and strength was so poor. None of these things are in her life now. I hope you all experience these changes, and more. Experiment with the sulforaphane and garlic doses for yourself, what is right for one might not be the right blend for another. Read all you can find on sulfuraphane, with it’s cancer killing ability, I think they have only scratched the surface on it’s HDAC ability to create frataxin. GOOD LUCK EVERYONE, LET ME KNOW HOW IT’S HELPED YOU AND YOUR CHILDREN, TRY TO GET SOME INFO FROM SCRIPPS RESEARCH, I CAN’T GET THEM TO GIVE ME ANYMORE THAN I HAVE FOUND.

  5. Our daughter 32 years old, has FA. Thank you Gary for all your reporting, we will be ordering today and start garlic and sulforaphane. Please keep up with your postings and we will do the same. Looking forward to hear from you. Thanks A Lot !!!!!

  6. Hello friends,
    My brother 18 years old, has FA .Thanksfor your reporting.We will start garlic and sulforaphane therapy.
    Dear Gary,how are your daughter? I am eagerly waiting for GOOD NEWS!
    thanks a lot.

  7. Gary,Antoni, such as further changes? I am very interested in everything in the area of ‘research’, I also have FA, I soon started taking Broculu (1000 mg daily), I intend to, and garlic pills but I’m still interested in your news … .. they are encouraging … with love -Maja

  8. Pam,
    Yes, she still purchases it from Puritan’s Pride, and she just increased her dosage to 4- 1000 mg pills per day this week.

    I apologize, I’m sorry for coming on so strong, but I believe it will help your child, and I am glad to hear you probably will try it, Thank You.

  9. I’m sorry Gary; my bad english often is not enough to explain well what I want to say.
    My mean of “subjective” was that it possibly didn’t work with all patients but just only with some patients (as all drugs …).
    My mean was not that it was just only a your daughter feeling (as placebo effect…) .
    I’m happy to see you so sure and satisfacted and probably I will try it too.

  10. Antonio,
    It’s not subjective that my daughter can move her toes, when she could not for 5 years. It’s not subjective when she was in a wheel chair for months, and now she uses her walker. It’s not subjective when she can feel the textures with her feet when she could not for a long time, or the fact that her feet are not blue and cold anymore. We tried other things, vitamin E, Idebenone, and all we got were complaints about it not working from her.
    The garlic Courtney was taking has many compounds in it, I am not claiming to be an expert in chemistry, but I have read that garlic is one of the MOST POWERFUL HDAC inhibitors, WHAT DO I HAVE TO SAY TO YOU ANTONIO TO AT LEAST GET YOU TO TRY IT, I THOUGHT YOU WOULD HAVE DONE IT BY NOW, WHAT ARE YOU WAITING FOR, STOP PROCRASTINATING AND TRY IT, EVEN LITTLE THINGS MEAN ALOT TO YOUR CHILD.

  11. Sorry Antonio,
    I haven’t checked back in for a while. Courtney is doing the same, she doesn’t use a wheel chair anymore, she uses a walker and she can feel things with her feet and toes because she has feelings in them, she feels good, she’s always in a good mood, but that’s just Courtney, but all things considered, she has not dropped down in anything I’ve told you before, she is holding her own very well. She only takes 3 garlic pills a day since we changed from odorless, to regular garlic, the 10 pills made her brake out on her lip, so she has cut back, but with no other affect. She still takes sulforaphane. We are happy that she still is doing the same. How are your children doing, Antonio, or anyone reading this, are they taking garlic or sulforaphane, what is happening with them.

    1. My son is on sulforaphane since June 2010 (1000 mg broccoli sprouts daily, that should be near to 20 mg of sulforaphane daily).
      He’s not on Garlic.
      We haven’t noticed improvements and my thougth is that FA progression is moving forward.
      I’m not sure that garlic is so important , seeing that you saw first improvements taking odorless garlic that you after discovered being not effective.
      Anyway, we will continue with sulfo a couple of moths more , maybe adding garlic soon.
      But my fear is that, as a lot of supplements/drugs more, the effectiveness can be very subjective and different beetwen patients….and in this case it’s possible that it could work for one and not for another one.
      I hope that it could continue to be useful for your daughter (and that could begin to be useful for my son too, of course; but I’ve some doubts about…).

  12. Any news from Gary about Sulforaphane “trial” with not odorless garlic added ???
    Is it better than before? Does your daughter mantain her improvements??
    Any update/experience from other ones??
    Thank you

  13. Veneta,
    I’m sorry I didn’t answer your other question about side effects. No side effects, these are natural products. You should keep garlic below 10,000 or 12,000 mg per day. My daughter now takes 2-5000 mg garlic per day, take them with meals and you can split it up one in morning one in evening. Don’t take them when you go to bed, they can cause you to burp. Take them with your evening meal, hours before you go to bed, you will smell a little for a few hours, but it’s worth it. See the directions for sulforaphane on the May 13 date.
    Good Luck Everyone!

  14. Veneta,
    Look above on my name on May 13 and you will see my places I buy from, but make sure you don’t use the odorless garlic, use the regular garlic that has all the compounds in it that makes it an HDAC inhibitor.

  15. Gary,
    I am 22 year old girl from Bulgaria and have FA, too.I’ve read about the drugs you give to your daughter and we want to try them.Can you give us a link where we can order them?Can you tell us if there is any side effects from the broccoli and garlic pills?Thank you and I’m looking for your answer!!

  16. To everyone:
    I just made a discovery about odorless garlic pills, don’t buy them, they do not contain Allyl Mercaptan, which is where the smell comes from and also where the HDAC inhibitors come from. I switched my daughter today to pills from Puritans Pride that are not odorless. Hopefully we will see bigger changes. Give it a try. ( This is a learning process for all of us)

    1. So, improvements you’ve noticed until now after sulforaphane and garlic treatment, should come only from the first one ….
      Please, let me up-dated about your future choiches with garlic and its possibles major effects…
      Thank you

  17. Antonio,
    I forgot to mention this, but Idebenone has not been shown to be effective in Canada’s tests they did, I think they concluded that last year. I had Courtney on this as well until I found out about it, like you, I found it did nothing for my daughter. Please check it out for yourself.

    1. Gary,
      I decided to not include garlic to get a better understandig about possible efficacy of sulforaphane as single compound .
      Anyway, it seemed to me that the “star of the show” was this second one and not the forst one.
      But probably we will consider to use both togheter in the near future.
      About Idebenone, as Canada/Usa trial you mentioned , also the European one recently completed has get a disappointing conclusions .
      Despite it, almost every neurologist in the world I’ve known should use idebenone (at least at 20/30 mg /kg /daily…) if his son/daughter had FA….
      As sulforaphane and garlic, Idebenone is well tolerated too ; and more : many families worlwide are noticing its possible positive effect on heart troubles .
      Thus……I will use it again .

  18. Antonio,
    It doesn’t sound like you have introduced garlic, in odorless pill form ,in your regiment. Look at the answers I’ve given on that , and why not include it, it might be the missing piece of the puzzle for you. I’m sure you’ve seen it’s all over the internet about it’s HDAC inhibitor affect.

  19. Antonio said: You are in right. I rewiew your comments and you never speak about Hdac type/number involved. It was just my (wrong) understanding or more probably it was simply my ….hope.

    Antonio, here is the research article link kindly supplied by Juan Carlos Baiges dealing with the HDAC type number involved, with induction of histone H3 and H4 acetylation.


  20. Gary, I’m truly happy to listen it .
    I’m with you when you say it hopefully could ,at least , keep her on slow disease progression until a cure can be found : this is exactly what I’m finding in Idebenone, Vit. E, ….and perhaps in Sulforaphane too.. No miracles, but something that could help our sons to fight better vs. FA, waiting for a real and more effective treatment (even if what you are reporting about your daughter is not too far from a miracle…)
    Anyway, my son is on Sulfaraphane since 45 days ago and sincerely we noticed nothing as important as you noticed with your Coutney …..
    But we will try at least for some months more.

  21. antonio,
    Courtney rarely uses her wheel chair anymore, she was just starting to use it for outside the house for about three months when we started her on garlic and suforaphane. In the last 4 months, I think she said she used it once at a birthday party, she generally uses a walker or walks by balancing herself and holding on to walls. I asked her today if she felt at the same level she was 6 months ago, getting better, or doing worse. She thought she was doing better than 6 months ago, because within the last week she said she can fell the muscles in the calves of her legs, she has been doing alot more walking, and she can really fell it now, as opposed to them feeling numb, and she is able to move her toes back and forth in a wider range. I mentioned that several months ago she said the feeling in her feet came back and she could tell textures with her feet, like carpet as opposed to tile, and pin pricks from the doctor on her feet, and moving her big toe and the toe near it like a scissor action, she could not do that for 5 years she said. Also she said she hasn’t fallen in 3 weeks, because she says she feels stronger. So all and all she is doing better and from what I have seen she is, and hopefully this will, at least, keep her on slow progression in an upward direction until a complete cure can be found.
    How about you antonio, and anyone else, has anything like this happened for you all yet, I hope so.

  22. Gary,
    You are in right.
    I rewiew your comments and you never speak about Hdac type/number involved.
    It was just my (wrong) understanding or more probably it was simply my ….hope.
    Anyway, what about your home sulforaphane trial???

  23. antonio,
    I don’t see in any reply where I said sulforaphane or garlic was an HDAC3 or an HDAC4. All I said was that they are HDAC inhibitors. I don’t know what the HDAC3 compound is. I’ve looked up the terms and asked some people I know about it, one was my doctor, and he didn’t know. Does anyone know a chemist that could tell us all what compounds #1 #2 #3 is, or what they come from.

    1. Hi all,

      As far as I am aware, compounds 1 and 2 above are chemically synthesised molecules. Compound 3 was constructed to use as a research tool to identify the biochemical target of compounds 1 and 2.

      In May this year, Repligen/Scripps filed an Investigational New Drug Application with the FDA to commence Phase I trials of their HDAC3 inhibitor, RG2833 (structure not disclosed). The compound was also granted orphan drug status (you can see the press release here). The first studies will be in healthy volunteers.

  24. Thank you Gary.
    I’m not able to find in these articles any relationship between Sulforaphane and HDAC (3 or 4) , or between Garlic and Hdac (3 or 4).
    Can you copy and attach the correct part of them???
    Thank you again.

    PS Any interesting news about your Sulfaraphane+garlic “Home trial”???

  25. antonio,
    Sorry I have not checked back in such a while. Anyway, the articles that I have read and re-read are:
    #1 Scripps research team reverses friedreich’s ataxia defect in cell culture.

    #2 Garlic-derived anticancer agents structure and biological activity of ajoene.

    #3 Ajoene, an experimental anti-leukemic drug mechanism of cell death. ( This is one of the best ones)

  26. Gary,
    you said that : “……sulforaphane, which is from broccoli sprouts, it is being used successfully on cancer treatment by big pharmacutcals. And when they were testing on white blood cells, they found out that frataxin was created in the cells as a by product……” and that “……sulforaphane or garlic as HDAC inhibitors, I found that on other sites, you can punch it in as read about it. What you will see is that both are HDAC inhibitors which create frataxin……..”.
    Please, can you send me the articles where you read it?? (or say me where I can get it)
    Thank you

  27. Antonio:

    What I understand is that “sulforaphame glucosinate” is the way that they find it in the sprouts, more pure, when it bonds with some other molecule it is called just “sulforaphame”. What I don´t undestand is why in some bottles they say mg, and others %.

    Anyway in conclusion what pills do you all think I should buy??

    Cristian FA, 29 years old

    1. Pam,
      my doubts are about that “Glucosinate” . I don’t know if quantity of Sulforaphane is the same quantity of Sulforaphane “Glucosinate”.
      Can you clarify this ?
      Anyway, may anyone buy on line at Ximogen web site, or only health professionals????
      Thank you

  28. We started buying brocco sprouts produced by this company from this website:
    Because the sprouts aren’t readily available and also because they are not always fresh, we are now going to order the supplements:
    We are still waiting to get the first shipment but while eating the sprouts, there did seem to be some improvement in feeling in my son’s feet.
    You can get pills that provide 30mg of sulforaphane or 100 mg of sulforaphane.
    Have you looked into this one Gary?

    1. Please Pam, can you check better sulforaphane quantity in each pill ? Dosage is very important and it seems impossible that a single pill (which weight??) could contain 30 or 100 mg of sulforaphane….
      Thank you

  29. Antonio,
    My May 27 comment refers to two tenths of a percent of each pill being sulforaphane. I’m in America and so far this is as potent as I have found. I may be looking to Europe to find 2%, the pills I have found are not that strong. Also, I was using a period and not a comma by the 2, just to clarify, my figures are correct for my bottle of pills, but if yours says 2% you are getting alot more sulforaphane, I don’t see that as a problem, check with your doctor, but I think it’s a good thing, if I had that pill strength , my daughter would be taking them. I hope I have explained myself better that time.

    1. Thank you Gary.
      Anyway, Solgar that suggested Mary seems to be at 2% of sulfaraphane too.
      Let us informed about any interesting news of your “private trial”.
      I will do the same if I will decide to start .

  30. Hi again,
    the brand which is easiest for us to buy is Solgar 500mg (2% Sulforaphane) 50 Pills
    Price: 33 Euros.
    Will keep you updated
    Good luck to all and THANK YOU FOR SHARING!!!

  31. I cannot understand well your numbers, but I suppose you are sayng me that a single 250 mg. broccoli sprouts capsule contains 0,21% of sulporaphane; that means 0,525 mg of sulforaphane, that means 2,1 mg of sulforaphane in 4 (1000 mg total) broccoli sprouts capsules ; thus just only 4,2 mg of sulforaphane daily, in 8 broccoli sprouts capsules (2000 mg total) .
    I think you’ve to be in wrong…Possibly your 0,21% has to be corrected in 2,1%…
    In fact, European suppliers are selling Broccoli sprouts extract with 2% of sulforaphane, that means 40 mg of sulforaphane daily in 2000 mg of broccoli sprouts pills).
    Can you chek it better in your bottles? It’s important.
    Thank you

  32. Antonio, reading the bottle, it appears that each 250mg pill contains .21% sulforaphane, which is .0021 times 250mg = .525 mg of sulforaphane per pill. They advertise that they are the highest rated around. I don’t know if that’s the case, if you can find something more potent, it’s worth a shot. Please speak to your doctor about anything you or your children take. Although this is derived from broccoli sprouts.

  33. Thank you very much Gary for this info.
    I haven´t checked other sites in detail; just wanted to be sure that I get a high quality product (I´ve noticed there are different brands and different prices).

  34. Just a question, Gary : you spoke about 2000 mg daily of broccoli sprouts extract , but it isn’t the same of 2000 mg of sulphorafane.
    In the highest concentration of broccoli sprouts there is a 2% of Sulphorafane, that means 40 mg of sulphorafane every 2000 mg of Broccoli sprouts extract….
    Is it correct??
    Thank you again

  35. Mary, that looks like the company I buy from. Their full name is” Living Whole Foods,Inc. Handy Pantry, Wheatgrass & Herb Kits”. They are in Springville, UT. ph. 1-800-735-0630
    The pills are called Broccoli Capsules- 250mg each pill( which is sulforaphane) Try calling the 800 number to be sure. I hope you can get them,
    PS Have you checked out other sites about HDAC inhibitors that create frataxin in the genes and also fights cancer, just curious.

  36. TO: Pam, Mary, Antonio,and Ralph I have not checked back in to this site in a while, I apologize. I will try to answer everyone’s questions. My daughter, Courtney, takes 1000mg of sulforaphane, which comes from broccoli sprouts, in the morning and she repeats that in the evening, a total of 2000 mg a day. We purchase this from ” Living Whole Foods, Inc. Springville, UT 1800-735-0630. We get the 250 mg capsules. She also takes garlic pills, 12000 mg per day, half in morning half in evening. We buy 1000 mg from Puritans Pride 1800-645-1030, they also have a web site. These two pills are HDAC inhibitors that was and is being experimented with to stop the spread of cancer, that’s how they found out that HDAC produced frataxin, as we all know, that is lacking in FA patients. Courtney has taken CQ-10, from Puritan’s Pride, 600 mg pills- 1200 mg per day that has helped to keep her heart and joints in good shape. I have been researching on the internet for ten years and I happened on this over a year ago. It was on the Scripps Pharmaceutical Co by Dr Gottlebb I believe was his name, please find this site and read for yourself. He does not talk about sulforaphane or garlic as HDAC inhibitors, I found that on other sites, you can punch it in as read about it. What you will see is that both are HDAC inhibitors which create frataxin. The book that gave me alot of info about garlic was Shane Ellison’s book ” OVER THE COUNTER NATURAL CURES”. This book speaks of the healing power of garlic down through the centuries, and that a person can take 12000 mg a day without any problem. I have been experimenting with sulforaphane and talking with a professor from Australia that writes articles in “GENERATIONS”, a FA magazine. He has not prescribed anything, but found out , behind the scenes , that these two pills were being experimented with for FA. Both pills come from natural plants: garlic and broccoli sprouts, so I personally figured they could only do so much harm, and apparently alot of good. I did speak with 2 doctors and told them what we were doing, they didn’t seem to have a problem with it, but that is something everyone has to do for themselves.
    Courtney has been able to move her big toe back and forth, something she has not done for 5 years, her walking improvements have plateaued, but but she is still doing well, and she can feel textures with her feet and hands and fingers, her feet and hands use to turn blue and felt like they were freezing but they are pink and warm and sweat on occasions. We feel like this is a shotgun type of help for Courtney that hopefully is being perfected to go right to the problem, which is what Generations magazine says is happening. But until that happens, this is a great help for anyone’s child because in my opinion, it stops FA from progressing and actually helps with symtoms in many ways, please try it, but work your way up to these dosages over a period of weeks because they can cause diarrhea.
    I hope this helps everyone, and again good luck to us all.

    1. Hi
      My sister and I have FA and we want to try broccoli and garlic but we dont know how to take it?
      Since broccoli contains 2,5% sulforaphane it means a pill with 1000 mg broccoli = 25 mg sulforaphane??????????????
      Is 2000 mg broccoli enough?

  37. Gary,
    Can you update us on Courtney and tell us how much Sulforaphane and garlic she is taking? In what form is the garlic? Does she take any other supplements?

  38. Hi all,
    I´ve been reading with great interest about garlic and sulforaphane. My daughter, 19, has Friedreich ataxia.
    I would like to test this Sulforaphane. Could you please give me more details: where to buy it, the commercial name etc

  39. Debbie,
    My daughters name is Courtney. And I want to tell you specifically what my daughter is taking. She is on sulforaphane, which is from broccoli sprouts, it is being used successfully on cancer treatment by big pharmacutcals. And when they were testing on white blood cells, they found out that frataxin was created in the cells as a by product. My daughter has not felt the doctor do pin prick tests on her feet and hands for 3 years, until last week. The doctor was amazed ,and said that shouldn’t be. She now can tell where her feet are when walking, they felt numb before. Her walking is getting better, and she hasn’t fallen down since she has been on garlic pills and broccoli sprout capsules. Look on the web for the most pure and without insecticides, you can find them. If this works for cancer, and it’s not on the market by big pharma yet, it’s because they haven’t found a way to tweak it yet so they can sell it. Please try it, it works. My daughter was walking better the same day she started taking the garlic and sulforaphane, I hope you all have the same results.

    1. Hi Gary,
      My son has FA and we’re from Italy.
      A “couple” of questions, similar to other I suppose you’ve yet received….
      How much Sulforaphane and Garlic does Courtney use daily ?? Was the dosage suggested by a doctor or by your(her)self ?? Any adverse effect until now (how much time using it?)?? More improvements since your last update??
      Thank you

  40. Thank you for your message on FA, what is your daughter’s name? my daughter’s name is Rachel she’s 34, And her eyesite and hearing is starting to go, but I’ll never give up and I’ll pray for us all, like you said GOOD LUCK TO US ALL.

  41. Charles and Debbie
    My daughter, age 20, has FA and I have found on the net that garlic and sulforaphane are histone deacetylases inhibitors. My daughter is increasing her dosage weekly, and is getting stronger. I don’t know if these are the #3 compound, but I, like you, are still looking. I am going to take this third formulae and ask my doctor to tell me what natural compound it is. GOOD LUCK TO US ALL.

  42. My mother has FA and is 61 years old. She has been fully dependent for her ADL’s since 24 yrs old.
    We are currently seeking more specific information on the progression in late stages when there is no heart involvement.
    She is in the hospital currently and has been there 5 weeks now. She developed a paralytic illeus and is having a hard time recovering. She originally had a small bowel obstruction and had a laprascopic proceedure to correct that…. so we are unsure whether this is just continuing d/t immobility or if it is in fact a progression of the disease.
    thank you- Charles Adair

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