SCA3 gene silencing

[Zephyr10]

I am happy to share what i just found. Might give me some hopes regarding my father too?

onlinelibrary.wiley.com/doi...

[Larobby]

Thanks for sharing! It would be good to keep this thread alive with any new articles we find. My brother has SCA but we don’t know which type yet, I am hoping that once we know we can enroll him into clinical trials. This is fantastic news anyway as it gives us all hope that science might crack this nut eventually!

[Sunny8088 in reply to Larobby]

We should make some more noise & awareness about this otherwise from mice to men it will take 10-15 years

[TonySCA3]

Thanks - good to see something with positive results..... in mice anyway.

And I agree with Sunny8088!

[Zephyr10 in reply to TonySCA3]

Im going to send an email to them and Ask wheb They are doing human trials. I suggest everyone should talk to their GP and Ask them to enquire about it?

[Litty]

Thanks for sharing, fingers crossed x

[Zephyr10]

I have some positive news i hope - i just got a response from the lead researcher. I asked about timeline and funding.

Hi Lilli,

Thank you for contacting me. I can tell you we are working hard on very promising treatment leads, specifically in collaboration with Ionis Pharmaceuticals. This work is very much in line with the studies completed for Huntington's Disease (HD). We are seeking a similar trajectory as the HD preclinical and clinical development, although thankfully the HD studies have smoothed the pipeline a bit. To speak toward the timeline and funding environment, we were recently awarded (April) an U01 NIH Optimization Track grant (four year grant) that will develop the lead SCA3 candidate for clinical trials and establishing strong SCA3 disease biomarkers to help quantify the effectiveness of treatment in future clinical trials. I honestly cannot predict the total funding costs, but every little bit helps!

Now I sent a respons if the possibility of establishing an international fund for this cause. For all SCA types! If we could get it on social media and establish funding we could look at a 4 year timeline before clinical trials. And get people of all onsets included.

Best Regards

Lilli

[sunvox]

Sorry to burst everyone's bubble, but this angle of research has been ongoing for almost 2 decades and at numerous different research facilities. The drug they have lined up for Huntington's is first in line and at least 5 years away from making it to market and more importantly it's an injection in the spinal cord once a month or more every month - for life AND the cost will initially be in the $100,000+ range per year - for your whole life.

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This is but one example of the overall group of treatments known as "gene therapy". I do believe someday gene therapies will be common, but not in the next decade.

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Sorry

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Joe

[Zephyr10 in reply to sunvox]

Hi Joe - have you read the research paper? The reply from the main researcher also refered to the HD results. I understand the commercial point of view for the sponsor who is paying for the research. I live in a country which Will actually benefit from paying for this shot AS the cost of a person in care is greater than the medical cost. This is an important aspect.

[sunvox in reply to Zephyr10]

Hi Z -

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Yes, read the paper. Although I am pleased to learn that your home country is generous in it's payment of medial care (do you by chance live in Israel - Tel Aviv is one of my favorite cities ), I fear few countries will pay that kind of money whether in a shot or in care. I am always happy to see research that is progressing towards a "cure", but I just want folks that actually HAVE a genetically inherited ataxia to realize this is a long, long . . . long way off, and more importantly it involves a serious medical procedure each month or more for the rest of their lives.

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I believe we can do better today by pushing people to make difficult lifestyle changes including hard exercise, an optimized diet, and scientifically proven supplements.

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In addition, the real hard truth is that with genetic testing we, as in humanity, have the means to eradicate genetically identifiable diseases in the next generation. That may be too much for some to accept, but it is a scientific truth.

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Joe

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P.S. Are you familiar with my story? As a potential inheritor of the SCA3 gene, I believe I have uncovered a "cure" for people like you and your brothers who may have the gene, BUT the earlier you find out and the earlier you work at prevention the better your chances will be to live a "normal" lifespan.

[ataxiathrowaway in reply to sunvox]

I disagree. While the proof of concept has been present for decades, these types of trials have not. We are seeing in real-time the first clinical trial that indicates a lowering of a toxic protein characterized by a polyglutamate disease (Huntington’s); a victory across the board for everyone suffering from an inherited, expanded-PolyQ disease. How could someone suggest that this isn’t something worth getting excited about?

I’m equally tired of seeing Ataxia get cured in mice, but that’s not to say the gears haven’t been moving in the clinics. Last year, we got to see the Trigriluzole trial executed gracefully, and while the topline results were negative (though this point is argumentative, as it remains to be seen how this drug impacts each specific type of ataxia, as type 1 patients were much more responsive), ataxians and clinicians alike were able to demonstrate that they can successfully coordinate a clinical trial for Ataxia on a national level.

To be clear, you, nor Ionis, can yet assess the effective dose nor the dosing windows, so it doesn't do anyone any good to assert that they will be receiving these injections monthly- much less provide your estimated cost of therapy. In previous trials we've coordinated, monthly dosing is usually prescribed mostly as a means of control- not because the therapy expires outside of a monthly window. It allows for frequent checkups, which is paramount in trials such as this where broad-dose distributions are used to assess potential tradeoffs of efficacy and safety. Some patients get higher concentrations of the therapeutics, while some get lower ones. As these studies progress, new angles regarding dosing windows are introduced, usually reliant on preclinical data with non-human primates as a baseline, so clinicians can then begin to optimize disease treatment and prevention based on disease phenotypes and other biomarkers. Monthly dosing can quickly turn into bi-annual, and as these projects gain traction, administration becomes more sophisticated and common, and costs are often driven down.

In my line of work, I have the luxury of working very closely with some of the folks at Ionis and the HTTRx molecule in their pipeline. Huntington’s may be “first in line,” insofar as a trial is already underway, but that’s not to say that they can’t run multiple ASO trials concurrently, so there’s really nothing keeping SCA treatments from their radar. Simply put, Ionis is a company who knows what they're doing when it comes to ASOs. They made a huge splash in recent years with Spinomuscular Atrophy. They’re exactly the type of people I’d hoped to see working on this sort of thing, and I’ll chalk it up as good news to see that they may have taken interest already. I’m not worried about this drug making it to market with haste, as there’s rarely a major paradigm shift for orphan drug indications between clinical III and IV/commercial launch; especially because these projects tend to get fast-tracked when they show the slightest hint of amelioration. As data is gathered and these mysteries unravel, higher dosages administered with greater accuracy often mitigate tight dosing windows. It’s worth considering that a lot of this investigative optimization occurs once the drug has reached stage IV/commercial development, so while it may be fair for you to say that we won’t see a broad-spectrum Ataxia cure until another decade or so, we are already seeing targeted therapies for PolyQ diseases literally for the first time ever, so this is definitely not pie in the sky. It’s real, it’s here, and sure- it’ll take awhile, but dammit do we have every reason to be excited about it.

[sunvox in reply to ataxiathrowaway]

Let me start by saying thank you from the bottom of my heart. I'm not sure what your exact role is with Ionis, but is is a genuine pleasure to have someone on the "inside" post on this forum. Again, thank you!

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Now having said that I'd like to respond on a couple levels. First, I want to explain my reason for posting a little better. Many if not a large majority of folks posting in the ataxia forum are over 60 and have varying forms of ataxia that are idiopathic. I think the minority of posters are individuals with genetically identified SCAs, and most importantly although I appreciate the enthusiasm in regards to the breakthrough I stick to my belief that the development and execution of this technology is bound molecule by molecule to one polyQ disorder at a time. As of today there are more than 2 dozen such disorders and who is to say if SCA3 will be 2nd or 10th in line meaning real treatments for most genetically inherited SCAs are still at least a decade or more away. For a patient that is in their late 50s or early 60s or even their 70s such treatments are interesting but honestly not of much hope. Now for my children who are in their teens I think this news is outstanding, but then I have always believed that science will find a cure for their generation.

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That brings me to my next point. I, also, am frustrated that patients and doctors are focused on the "silver bullet" when there is mounting evidence that doctors are leaving a great deal of relevant therapy on the table. I am in contact with Dr. Jeremy Schmahmann from Harvard Med who is one of the leaders in SCA1 and related disease research. After reviewing my case and my family's story he agrees doctors have been slow to recognize that much can be done to help patients in terms of healthy lifestyle choices and basic physical therapy, especially for the generation of folks who have a genetic diagnosis and few or no symptoms as of yet. That is my second reason for posting. On this forum, I find many people who have yet to adopt the most basic changes in their lifestyle that are proven NOW to delay the onset of their illness, and I fear that announcements like those at the beginning of this discussion only lead to further procrastination when action is critical.

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So, again, as I said, I am excited and pleased to have a scientific voice on the forum and thank you for your post, but I hope my diatribe helps explain my position a little better.

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Joe in NY

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P.S. I have SCA1 with a CAG count of 42 but have zero symptoms. I and other family members are controlling our progression. Part of the story is here if you are interested:

healthunlocked.com/ataxia-u....

[Zephyr10 in reply to sunvox]

I know your history - you have an expansion of 40? My father has 64 - my grandfather hardly had any symptoms - he walked with a cane. My father cannot walk. I’m just saying it is different for each generation. And my generation will have it even more prominent. But I will heed your advice - I’m spreading your knowledge to my family - but at the same time I’m overly excited about any progress on behalf of the rest of my family and I hope both HD and any other dominant genetic disorder is wiped out 👌

[sunvox in reply to Zephyr10]

Hi Z - I assume, perhaps incorrectly, from your post that your family has SCA3. The number of CAG counts that are considered pathogenic vary by SCA. SCA1 has a threshold of 37 while SCA3 has a threshold of 61. 64 is low for SCA3 and corresponds to an onset after age 60. My 42 count corresponds to an onset in the mid-40s. There are tables that have published ranges for some SCAs and the CAG counts, but as you indicate there is variability in onset, and THAT is my whole reason for being on this forum because I believe people with a genetic diagnosis who do not yet have symptoms have much they can do to delay the onset. Also, I agree completely that I hope these disorders will be wiped out, but I must be honest as at least for my family I am certain it will be. It is trivial to have a DNA test performed on an embryo to determine whether or not it carries the flaw so I assume that my children (should they later learn they carry the genetic flaw) will avail themselves of that technology when the time comes for them to have their own children, and by doing so ensure they do not pass on the gene to the next generation. Of course, I am aware that not everyone will look upon such a solution with favor. Joe

[ataxiathrowaway in reply to sunvox]

Thanks for your reply. Without giving too much away, I work with Ionis to ensure their drugs are filled into vials without the risk of contamination, and I’m currently earning my masters in Biostatistics, so I have the opportunity to see a lot of clinical trials similar to HTTRx take shape. I occasionally peruse these forums for I myself am an SCA1 patient, but forgive me for not recognizing that most of the patrons here have a CA that’s idiopathic in nature. I suppose I should clarify- there is enormous implication for folks with a clear, single-gene mutation in these trials (like SCA1, 2, 3, 7, etc.), but yes, sadly the hard truth remains that therapies such as these are specific to patients with an Ataxia of a well-understood origin. Any condition without a clear, consistent cause will always be more difficult to treat.

Apologies, as my goal was not to sound contentious- you’re obviously well-versed in the literature behind Ataxia, and this community owes you a great deal for your armchair research! It's just that my impression was that your tone was far too pessimistic for those with a condition like mine when you consider the quickened pace in studying these conditions in recent years, but now I see your point, given the audience.

Anywho, despite my immersion in these trials and the work associated with them, I’m a huge proponent of proactivity about personal health. I too firmly believe that with these types of disorders, you don’t only need to be your own advocate- you need to be your own scientist. It requires action from every angle, even after the science arrives (better late than never). A conscious diet, rigorous exercise, enough sleep, and proper supplementation should always be in your regimen.

A common theme with the ataxias is that there is “no known cure” or “no known treatment,” but I’m sure you would agree that, unfortunately, most patients don’t realize that this statement is to be taken with a quarry-sized grain of salt. Clinicians technically do not have the authority to declare a multi-faceted approach to neurological disease as a viable form of treatment, as there is no data to suggest that it is. Until a clinical trial comes along that accounts for the "entourage" effect of a healthy lifestyle with ataxia-specific supplementation, none can say what works. Sadly, Ataxia trials in the past have been too small and disorganized to draw any meaningful conclusions from, so instead it's up to the patients to read between the lines and follow common themes in neurological disease.

In fact, I take many of the compounds that you've written about. Insofar as there aren't any majorly deleterious side effects, I don't seem the harm in us trying to weather the storm until something more concrete arrives. My only concerns are that these compounds may have a low bioavailability or cannot reasonably reach affected areas, and that their interactions are not well-documented. Cell signaling is extremely complicated, but since we'll likely never be able to shed much light on the effects of these compounds in humans with Ataxia (especially because the disease can manifest very differently, even within the same lineage) we've no choice but throw caution to the wind in lieu of these neurological cocktails.

I'm not confident it will halt progression altogether, but as someone who's in only the earliest stages, I'll do everything in my power to try to make that happen. Although I had to watch my father suffer without any personal intervention, (and now my brother, who's arm you'd have to twist to get him to exercise), I believe that DNA doesn't always hold your destiny. I refuse to go down the route that they have- at least, not without a fight!

[sunvox in reply to ataxiathrowaway]

Wow!

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Thanks for sharing. Obviously now you really have my attention since you have SCA1. Are you willing to share what your routine is right now? If you're uncomfortable posting it in public please feel free to drop me an email:

j o s e p h p e c k 1 9 6 6 at gmail

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Would love to start a totally new discussion and get your input on specific supplements and the strength of the research or lack there of in relation to the polyQ disorders!

[billiecorton in reply to ataxiathrowaway]

Do you know about the recent discovery at University College London that mutation on gene RFC1 is behind CANVAS, late onset ataxia, with neuropathy and vestibular syndrome.

[billiecorton]

Very recent research (2019) at University College London has identified a recessive mutation gene expansion on gene RFC1 as behind many cases of late onset ataxia, recently thought to be idiopathic. Will research now focus on a possible treatment for this relatively common but previously mysterious condition?