I’m changing my tune and jumping on the CRISPR bandwagon, with the stipulation that for polyQ SCA, it must be futuristically deployed with viral delivery—i.e., nanoparticles cannot be effective enough. The time horizon for treating SCA(3) is beyond my lifetime, but at least it’s possible to imagine it working eventually on presymptomatic children. Neuronal death still can’t be reversed, and the CRISPR hype is almost unbearable.
To summarize the hype, there’s an impossible expectation that CRISPR will be effective on adults with extensive neuronal death, and there’s a truly bizarre celebration around the idea of using CRISPR together with IVF, with an obliviousness that this approach to pregnancy (with no need for CRISPR) has been available for over 20 years.
The key to CRISPR is viral delivery, either lentiviruses (LVs) or adeno-associated viruses (AAVs). Also see self-complementary AAVs (scAAVs). This is the missing piece so carefully omitted by the articles and interviews I’ve seen and heard. I missed this key for a few years. For non-viral delivery, the unspoken keyword is nanoparticles (SLNs).
2019-04-12. Example article that downplays (but does mention!) the necessary viral delivery. (Not directly related to SCA.)
CRISPR is a gene-editing tool, and that tool doesn’t include a delivery mechanism. If the delivery mechanism is non-viral, then it’s impossible to modify the 37 trillion cells in the human body, or the 171 billion cells in the human brain, or the 85 billion cells in the human cerebellum. But with viral delivery, reaching a high percentage of all cells becomes theoretically possible.
We can compute the theoretical number of iterations (generation times) to reach n cells, with virulence x (where x > 1; e.g., if x = 2, then on every iteration, twice as many cells are reached than on the previous iteration):
f(n, x) = logx n = log n / log x
f(37 trillion, 2) = 45
f(171 billion, 2) = 37
f(85 billion, 2) = 36
With perfect viral delivery, the number of iterations is theoretically realistic, e.g., 45 iterations to modify every cell in the human body, if reach only doubles on each iteration.
The main facet of this to come to terms with is: viral delivery is nowhere near perfect. Questions to explore: How many cells can really be reached while remaining potent, before the virus dies (the body fights off the virus eventually)? How science-fictiony is it to expect a drug to remain potent as the virus proliferates? Does the payload also need to replicate? How does that work, if at all?
Yikes: “Once used, the viral vector cannot be effectively used in the patient again because [an immunity is developed. For example,] if gene therapy fails in clinical trials, the virus can’t be used again in the patient for a different gene therapy in the future.”
As far as I tell, ASOs don’t use viral delivery and exist in a linear world of nanoparticles as opposed to an exponential world of viruses.
In short:
- CRISPR with non-viral delivery applies to modifying a small number of cells, such as the conception process, maybe tumorous cancer—i.e., not polyQ SCA.
- CRISPR with viral delivery applies to modifying mature organisms where billions or trillions of cells matter, such as with polyQ SCA.
- ASO (or CRISPR) with non-viral delivery with polyQ SCA: the fraction of affected cellular activity is staggeringly small and for ASO, temporary. This puts us into try-it-and-see mode, but the inevitability of genetic diseases such as polyQ SCA just being delayed or stretched out seems terribly obvious to me. Non-obviously, however, is that could be the point: this is considered a solid “win” if a disease is delayed past one’s lifetime and still a partial “win” if minimized during one’s lifetime.
Related
2024-01-23 podcast: Unlocking Gene Therapy with Guarav Shah.
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