Clearer Thoughts on a Cure

Some of the spinocerebellar ataxias, including SCA3, are genetically similar to Huntington’s disease (HD) in that they involve CAG repeats on a chromosome. I’ve found the HD community to be more informed and practical than the SCA community, where:

  • There’s not a misinformation campaign against accurately conveying disease prevalence, as there is for SCA.
    • Sadly, they do have their own special brand of nonsense, around a meaningless and fabricated at-risk prevalence number of 200,000.
  • They’re generally more informed and realize that brain degeneration cannot be undone.

Background

Blog content consolidated here.

Curability

Someone with SCA cannot be cured in the sense of ridding the genetic / neuronal / chromosomal problem from their body and/or brain, as the body is built on trillions of copies of the same genome. Perhaps, eventually, CRISPR with viral delivery will get close enough. In some circles, the phrase disease-modifying is replacing the word curing since the disease cannot literally be cured but will possibly be modifiable to some degree in the future. There are thousands of genetic diseases; not one has been “cured.”

For those with an SCA defect, there are two main cases to consider:

1. Being asymptomatic: The goal in this case is to live one’s life with the defect but never become symptomatic. This is the most desirable outcome for those with the defect.

There are some possibilities for achieving that:

  1. Gene silencing (such as antisense oligonucleotides or ASOs)—fixes the RNA but not the DNA. A weakness with what’s in trials for HD is that since its delivery is non-viral, we’re in wait-and-see mode on how effective it ends up being. Also, it’s not permanent. Partial and impermanent do not make a good combination. People are waiting essentially to see if it’s “good enough,” for something that will likely cost many millions of USD over time.
  2. Gene editing (CRISPR) with viral delivery, which has the theoretical potential to correct the DNA of billions of mature cells.

2. Being symptomatic: The goal in this case is to stop or at least slow the cerebellar degeneration. I think this is the likeliest achievable case, still decades out, and barely desirable. The desirability is low because symptoms won’t likely improve: if cerebellar degeneration can truly be halted (unlikely; slowed is more realistic), then symptoms could be frozen in time for the rest of one’s life and begin to interact with the aging process.

If slowing degeneration is the best case, then case 2 really equals case 1. Having the genetic defect but no disease symptoms means the symptoms are pending, unless you die first.

Interestingly, in 2018, there’s an effort to separate 1 and 2 and classify 1 as being “clinically ready,” which by implication classifies 2 as clinically hopeless, which accurately reflects the biological impossibility of fixing the problem.

Notes

There might end up being just one drug therapy approach that covers both cases above. Picture a world where everyone with the SCA(3) defect takes the same drug whether they have symptoms or not: those without symptoms hope not to develop them, and those with symptoms are in the nebulous territory of hoping not to worsen.

Symptoms are not an exact reflection of the cerebellar degeneration that has occurred (i.e., cell damage vs. cell death). External symptoms might occur years after cerebellar degeneration has begun. To remain symptom free, I’d guess that one with the defect would need to begin diligent drug therapy in early childhood or infancy, perhaps in utero. (Case in point: nusinersen; a more explicit example; another tangential example) If one waits until there are external symptoms, the amount of and permanence of cerebellar damage, and the momentum of the damage, might be insurmountable, especially as the aging process marches forward.

Someone taking medication to thwart symptoms in themselves can still pass on the defect to their offspring, via their sperm or ova. To avoid passing on the defect, the prevention ideas (below) must still be followed. As disappointing as it is, I imagine a future world where those with genetic diseases can mask them with a lifetime of medication, all the while passing on the defect to future generations, ensuring that the diseases are never eradicated.

The conundrum becomes this: slowing the disease to beyond one’s lifetime could be just as good as stopping it altogether, but how do we get there from here? Therapies will need to evolve for decades to achieve this result, yet the early, undesirable therapeutic stages will still cost millions of USD dollars yearly, making them even more undesirable.

Prevention

The only theoretically perfect long-term solution to SCA is prevention. “Perfect” means babies are born free of the defect. Anyone born with the defect must deal with it as they age. If they’ve been tested and understand their situation, I think they have an obligation to humanity to take evasive maneuvers in the procreation process, but some are strongly opposed to this idea.

Since the early to mid-1990s when DNA testing became available, we have had everything needed to rid the world of various SCA diseases in one generation, while still allowing for offspring. Prevention can only revolve around pregnancy (avoiding or modifying it). There is no other place in the life cycle to apply principles of prevention.

Here’s what’s working for us if you have an SCA defect and know the genetic specifics:

  • You can choose not to have offspring.
  • Genetic testing of zygotes, blastocysts, embryos, fetuses, children, and adults is possible, at any time (asymptomatic or symptomatic). In the context of prevention, this is important so that testing can be done at the fertilization or fetal stage of one’s potential offspring.
  • Amniocentesis followed by possible fetal abortion.
  • In vitro fertilization (IVF) with preimplantation genetic diagnosis (PGD), to avoid possible abortions.

Here’s what’s working against us :

  • The expense of genetic testing put it (and the items below) out of reach for many.
  • Possible religious opposition to fetal abortion.
  • The expense and nontrivial nature of IVF with PGD (USD 20,000 or so).
    • Possible religious opposition to destroying embryos, both the runoff (from IVF) and the rejected embryos (from PGD).
    • This technique isn’t guaranteed to result in a successful pregnancy. No technique is guaranteed.
  • Some are opposed to applying any technology to the procreation process. Some are opposed to using DNA testing as a tool.
  • If you have kids early and don’t know of the genetic defect, you won’t know any of this. Factors to consider here are if you don’t know who at least one of your parents was, or if the parent you inherited the defect from died without an SCA diagnosis.

It’s ironic that if drug therapies are developed that allow one to have SCA but not develop symptoms, I’d say it’s human nature to keep having kids without safeguards, thereby allowing the defect to exist in the world forever. I don’t think prevention will be achieved.

Does the work being done on therapies have a long-term vision of eradicating the diseases from future generations (no), or just of looking at the impact on the current generation (yes)? I’d say we are quite literally gearing up for humanity to have these diseases into the future with unwavering prevalence, possibly minimizing their impact on those willing and able to be tested and take million-dollar medication at an early age before becoming symptomatic.

SCA pipe dreams

The most well-known SCA pipe dream is anything involving stem cells. Stem cells will never be a part of a perfect SCA solution—maybe only aiding, indirectly, as an in vitro platform for drug testing, i.e., for growing things to test on (update: this became true in 2019). Maybe in the future (perhaps even now), stem cells safely injected directly into the brain will offer temporary improvements, but they will never prevent or eradicate the SCA problem in an individual. The new cells would only supplant glial cells and not preventatively replace portions (neurons) of one’s functioning cerebellum.

The up-and-coming SCA pipe dream is that non-viral CRISPR (i.e., gene editing) can help with it. CRISPR without a mechanism of delivery into mature organisms works at the zygote stage (even better at the fertilization stage), maybe getting into the blastocystic or embryonic stages. To fix SCA in an adult, a viral delivery mechanism is needed to fix the billions of neurons in a mature cerebellum.

Does non-viral CRISPR offer us with SCA anything over IVF with PGD, which has been available for 20+ years? No—it would still be used in conjunction with IVF and involve the discarding of unused embryos. IVF with PGD (available for 20+ years) can be used to discard zygotes that are determined to have a genetic defect, whereas single-cell CRISPR can theoretically fix a defective genome before cell replication begins.

I think that the latest fervor over antisense oligonucleotides (ASOs—a form of gene silencing, not gene editing) will be overtaken with CRISPR fever, because even though neither offers a perfect solution, CRISPR is theoretically better than ASOs: it’s suited to viral delivery, and it’s permanent—modifying the DNA in the genome, rather than leaving the defect in the DNA and affecting only the messenger RNA.

My follow-up on CRISPR.


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Comments

16 responses to “Clearer Thoughts on a Cure”

  1. Brian Law Avatar
    Brian Law

    Jens. In simple language, what mechanism, if that is the correct term, changes in the affected parts of our neurology for people such as myself with inherited SCA. Brian. What appears and why?

    1. Jens-Ingo Farley Avatar
      Jens-Ingo Farley

      It matters a lot which SCA type is of interest. I am close to 100% biased towards understanding SCA3, since that is what I have. I have encapsulated what I have learned and come across here: http://ataxia.hemiola.com/2017/09/12/can-you-repeat-that/.

  2. Quan Tran Avatar
    Quan Tran

    You mentioned stem cells as a pipe dream because they don’t form / replace neurons. And I understand there are ongoing debates on whether neurons regeneration could happen post embryonic stage. But what about embryonic stem cells? Or if morality becomes an issue (harvesting embryonic stem cells from an abortion), what do you think of adult stem cells reprogrammed to behave like embryonic stem cells? (I’m getting into pluripotency and multipotency here.) I also am aware of the current limitation of not being able to dictate what the stem cells differentiate into. Injecting someone’s brain with a vial of reprogrammed adult stem cells might just introduce a lump of hair and bone into their skull (tumor). The magic bullet would be reprogramming adult stem cells for unipotency of cerebellum neurons only. For reference, I have SCA-1, symptoms manifested about 3 years ago, and I’m just trying to read everything I can on the subject. I pretty read every post on your blog. Very informative stuff. Keep up the good work.

    1. Jens-Ingo Farley Avatar
      Jens-Ingo Farley

      I don’t see how stem cells can be used to prevent the disease. I don’t think the cerebellum can be proactively replaced with newly built neurons. Now to the question of repairing a partially degenerated cerebellum. Even if you were to manage to replace dead neurons with new ones from a donor or your own but repaired, it won’t stop the process of degeneration of the neurons that haven’t degenerated yet. So, best case is it for it to be partial or temporary. That is how I see it, anyway.

      1. Quan Tran Avatar
        Quan Tran

        Yeah. I agree with what you are saying completely. Standalone, stem cells injection would have to be a lifelong treatment ($$ sign to pharmaceutical companies). Maybe a monthly injection, assuming reprogramming and differentiating issues can be resolved. To simplify things, say you were losing cerebellar neurons at 10 million cells a day, the treatment should inject 10 millions to halt the disease. If toxicity negligible or tolerable, increase dosage to 20 million cells. Half to counter the loss, half to rebuild. Or some kind of number that the body can tolerate: 12 millions, 35 millions, etc. With Steminent Stemchymal entering phase III (according to clinicaltrials.gov Steminent finished phase II in February of 2018), hopefully we will have an answer to the dosing question soon. Perhaps combining stem cells injection with DNA / RNA editing (crisper / crunchier / steoreopure stuff) for a long term solution. As far as prevention, I think we would have to go all the way back to IVF and PGD as you mentioned in another article. And frankly, I think the government should step in and pay for the entire thing. Start an account and place the debt in the child’s name, with interest. Would I pay $20k to ensure I did not inherit SCA at conception? In a heartbeat. Without a second thought or any reservation. It might takes me a few years to pay it back, but I would pay it back. I’m digressing.

        1. Jens-Ingo Farley Avatar
          Jens-Ingo Farley

          I’d caution against getting too excited about Steminent, because I don’t think they can/do make any promises about replacing/supplanting neurons. Mesenchymal stem cells are not embryonic stem cells, yet even if they were, I’m not very hopeful that embryonic stem cells would do a good job repairing a degenerated adult cerebellum.

          Interesting thoughts about government-sponsored IVF + PGD. I hadn’t really allowed myself to think down that path, but doing so helped remind me of the imperfect nature of even that: some young parents will have kids without knowing any of this.

          1. Quan Tran Avatar
            Quan Tran

            Yes. Clinical trials are full of disappointments. Case in point: Biohaven. But, at this point, any shred of hope does wonder for my depression. That, in itself, is worth something. And, I think you mentioned somewhere that depression might not be caused by SCA in the pathology sense, but it might be caused by SCA in the psychology sense.

          2. Jens-Ingo Farley Avatar
            Jens-Ingo Farley

            My point is more that you can’t expect a clinical trial to do more than even the pharma company hopes for. Biohaven is trying to repurpose a +20-year-old drug, for both SCA and OCD. Steminent is trying to legitimize the illegitimate field of stem cell treatments, but they themselves don’t suggest they are doing more than boosting glial cell development, not neuron replacement.

  3. Quan Tran Avatar
    Quan Tran

    I was just musing about details on neuronal deaths. Where do they go? They can’t just lay around right? Are they still attach to the living part of the brain / cerebellum?

    If Steminent Stemchymal works as advertised (assuming no tumor and proper instruction to differentiate into new and replacement neurons for the cerebellum), how are they planning on cleaning up the dead neurons to make room for the replacements? Is it just an empty void in the cerebellum that Steminent is planning to fill with Stemchymal injections?

    Enter the Jedi(s):

    https://medicalxpress.com/news/2010-01-dead-neuron-clean-up-crew-peripheral.html

    1. Jens-Ingo Farley Avatar
      Jens-Ingo Farley

      Again, I would caution against expecting more from Steminent than they expect from themselves. They don’t talk about replacing neurons, as far as I can tell. Their adult-fat-tissue-derived stem cells aim to increase the cellular support system for ailing neurons, not replace them.

      I don’t mean to make it sound like I know more than I do, but I have used / defined the terms apoptosis, necrosis, autophagy, etc. on this site. My own theory / understanding / assumption for the reason polyQ SCA takes a few decades to show overtly is that SCA involves a failure of the process of cleaning up of dead neurons and takes a few decades to become noticeable, and in fact, the reason why SCA degradation is exponential (as opposed to linear) is exactly because dead neurons lie around and kill even more neurons.

  4. Quan Tran Avatar
    Quan Tran

    What if they saw open my skull, cleave off the bad portion of the cerebellum with some precision laser work, stitch everything back, inject my cerebellum with some replacement neurons (grew in a dish, cross-fingers no rejection)?

    Borderline Frankenstein, but, at this point, I’ll try anything. For the sake of science, right?

    I thought about transplanting an entire healthy cerebellum from an organ donor, but that would require billions of connections to be made. Probably not technically feasible for the foreseeable future. Maybe transplant, and let nature takes its course?

  5. Quan Tran Avatar
    Quan Tran

    What’s your thought(s) on the lack of regulations in China, and the fact that they can do whatever research they want? Good, bad, indifferent?

    The Chinese researchers are doing human trials with CRISPR technology while American firms are wading through FDA regulations.

    https://www.popsci.com/china-crispr-immunotherapy-fda

    I understand that standalone, CRISPR will not cure SCA’s, only halting it. Any pre-existing damage to the cerebellum will stay. If I’m already in a wheelchair, I will stay in the wheelchair. CRISPR, in the form of a “cutting drug” (I’m only interested in chopping off the CAG repeats to become normal, I don’t want to paste anything), would be great for pre-symptomatic SCA patients, and CRISPR would have to be combined with something else (partial cerebellum transplant?), for post-symptomatic SCA patients.

    If CRISPR can halt the disease progression while I wait for a “cure” to replace the dead neurons, I’m all for it.

    1. Jens-Ingo Farley Avatar
      Jens-Ingo Farley

      In the 1990s, when my DNA was tested, genetic counselors were taught to say that genetic diseases like SCA not only had no cure but were incurable. You could say that I came to peace with that idea over 20 years ago.

      I really have no idea if or when China will specifically address SCA3 (and other SCAs) with viral CRISPR in humans. They might be unencumbered by regulations and be making more progress with more things, but a highly specific version of it for SCA3, when there are thousands of other rare diseases? It seems doubtful to me. Eventually, financial incentives will play a part, too.

      (Side note: To go along with your Frankenstein idea, you yourself could try buying a CRISPR kit and rigging it yourself as needed.)

      https://www.scientificamerican.com/article/mail-order-crispr-kits-allow-absolutely-anyone-to-hack-dna/

      Look at gene silencing. It took 20 years in the U.S. to go from discovery to FDA approval, for both ASO and RNAi. Has China had any of those drugs available sooner? Not that I know of. Will CRISPR be different? Maybe; maybe not. I’m not sure anyone can know.

      My perception of lack of regulation is as follows: costly stem cells (mainly for foreigners) that don’t work have proliferated there, where there’s no regulation to keep them out of the system. I’m wary of expecting them to suddenly start producing effective drugs for all kinds of diseases.

      But, yes, at least conceptually, viral CRISPR in China is: science fiction I can believe in. I wouldn’t put all your eggs into that one basket, though.

  6. Quan Tran Avatar
    Quan Tran

    Lol @ the DIY toolkit.

    I wonder if American biotech firms could skip some of the precursory researches done for the more prevalent diseases (Alzheimer, Parkinson), especially after the Chinese already found treatments (I’m refraining from using the word cures here), for them, plagiarize the know-how, and gun straight for the rare diseases to enjoy the orphan drug benefits? Given that the Poly Q SCA’s all involve mis-folding proteins, it seems, at least theoretically, a drug for SCA-1 would need very minor tweaking to work for 2, 3, etc., because it would just be a question of where to cut based on what a healthy range of CAG repeats is. Non-Poly-Q SCA’s not included; I haven’t bothered learning their causes and effects.

    Case in point, my SCA-1 healthy range is 6 to 35 according to one article I read. Theoretically, making a cut at 30 would cease production of mutant proteins from all SCA-1 patients. Halting the disease, not quite curing it. Also, not pasting genetic code onto the cut sites has some advantages: Smaller package to deliver, lower chance of off-target mutation, to name a couple.

    1. Jens-Ingo Farley Avatar
      Jens-Ingo Farley

      It’s not like China is banging out the solutions, with the rest of the world sitting idly by. I think if China demonstrably and provably solved a big problem, like Alzheimer’s disease, streamlined partnerships would be inevitable.

      Small nit: the protein misfolding in the gene expression is not the thing corrected by CRISPR—the CAG repeats are fixed in the original DNA.

      I haven’t investigated CRISPR enough to know about snip-only vs. snip-and-replace, but what you say sounds reasonable.

      I’ve thought minimally about specificity of the applied CRISPR. How does it know what to target, and how precise does it need to be? Let’s say you get it into the brain, and it modifies the DNA in the whole brain and not just the cerebellum. No problem there, as far as I can see. The misfolded protein is a problem only in the cerebellum, but the DNA can be (over)fixed anywhere in the brain and body and should not be a problem.

      The idea of unleashing a virus into the brain to deliver CRISPR into billions of neurons is slightly disconcerting. With a non-viral treatment, perhaps monthly, you can just stop it if doesn’t work out. With a strong enough virus, there won’t be any turning back.

      If they make a Hollywood movie out of this, here’s my suggestion for the title: “A Change of Mind”.

  7. Quan Tran Avatar
    Quan Tran

    Haha, “A Change of Mind” literally and figuratively.

    In one of the articles I read, the speaker compared old gene editing methods (zinc finger, TALEN), to editing a DNA book by ripping out big blocks, page(s) at a time. Whereas, with CRISPR, the researchers are able to edit words, maybe even characters. Much higher precision, and much lower chance for off-target mutations. CRISPR is also much cheaper and simpler to construct and deliver, which partially explains the current boom of researchers attempting to apply the method.

    From a monetary standpoint, the bio-pharmaceutical companies would probably opt for a treatment that is temporary and lifelong. If it has to be one time, the pricing would probably be insane, like Luxturna.

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