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 more up-front about the impossibility of a gene-based cure, which I believe is a taboo subject in the world of SCA. It took me a few decades to unravel this basic notion, because there’s so much pressure to deny it in the world of SCA. That is the topic of this article.

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. 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 a fractional 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 two theoretical possibilities here for achieving that: (1) gene silencing—correcting the toxic protein as it’s created, and (2) counteracting the toxic protein that gets created before it damages the cerebellum.

There are a few glimmers of possible drug therapies, but it’s unwise to make long-term predictions. Given the unknown time horizon (decades?) and unknown effectiveness, limitations, and side-effects of future drugs, there’s the possibility that no solution like this will be developed.

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 is an effort to separate #1 and #2 and classify #1 as being “clinically ready,” which by implication seems to classify #2 as clinically hopeless.

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.) 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 it:

  • You can choose not to have offspring.
  • Genetic testing of 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 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 have a long-term vision of eradicating the diseases from future generations (no), or just looking at snake-oil 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 to be tested and take medication.

SCA pipe dreams

The most famous 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. 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 of one’s functioning cerebellum.

The up-and-coming SCA pipe dream is that CRISPR can help with it. CRISPR works at the zygote stage (even better at the fertilization stage), getting into the blastocystic or embryonic stages. But it’s science fiction to consider it able to fix the billions of neurons in a mature cerebellum with SCA.

The hype out there now is that CRISPR will be able to operate on mature organisms any day now. Even if that happens for certain body parts, swapping out parts of the brain is science fiction. Though it’s conceivable that (e.g.) hearts from genetically engineered pigs could be used in humans, it’s inconceivable to do the same for parts of the brain.

Does CRISPR even theoretically 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 CRISPR (now experimental only; considered human genetic engineering, which is banned now in the U.S.) is for changing (or “fixing”) the genome before cell replication begins.

I think that in the realm of gene silencing, the latest fervor over antisense oligonucleotides (ASOs) will be overtaken with CRISPR fever, because even though neither offers a perfect solution, CRISPR will be seen as better than ASOs because it’s more permanent—modifying the DNA in the genome, rather than the messenger RNA.

My follow-up on CRISPR.

2 Replies to “Clearer Thoughts on a Cure”

  1. 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?

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