Another form of gene silencing is RNA interference (RNAi) and was discovered 20 years later in 1998. It was heralded in the early 2000s as a candidate for SCA disease-modifying treatment. Both RNAi and ASOs have been successfully shown to quiet down polyglutamine gene expression in non-human tests, but I think RNAi tests stopped before getting to humans. In 2015, ASOs made it to human trials for Huntington’s disease (a hop, skip, and a jump away from SCA3), with safety established in 2017.
In 2017, a form of RNAi that is worth being aware of is “short/small hairpin RNA” or shRNA.
By any other name
From my tiny perspective, which is perhaps teetering on accuracy, this is what happened:
RNAi showed promise in the early 2000s but was dropped because of challenges with delivery (crossing the blood-brain barrier) and specificity (not throwing the baby out with the bathwater). The RNAi approach to dealing with SCA was either abandoned or put on the backburner.
Ten years passed.
Now researchers have achieved similar lab results after switching focus to an older technique involving ASOs and now face similar challenges with delivery and specificity but are working through them. To bypass the blood-brain barrier, they went from intracerebroventricular injection (ICBI) to intrathecal injection (spinal canal injection).
We’ve almost been here before, and who knows what will happen next, or if successful to any degree, how long it will take? My guess is that CRISPR will be the next distraction, leaving ASOs and their roadblocks on the backburner, and adding years to the exploration process.
There is a nucleotide in the affairs of men
Perhaps it’s the computer scientist in me, but the term RNA interference is self-explanatory enough to not feel the need to delve into what it precisely means. But I cannot stand by idly with the term antisense oligonucleotide, which to me is at first quite cryptic.
Sense in genetics is like voltage polarity in electronics, having positive and negative, where—continuing with the analogy—voltages can combine and cancel each other out. Antisense is like that: unwanted nucleotides in a genetic sequence (e.g., CAG repeats) can be silenced (i.e., erased) by applying the negative (i.e., complement) of that sequence.
What is an oligonucleotide? We know and accept that DNA consists of strands of C-G-A-T nucleotides. Oligo– is simply the Greek prefix meaning few (i.e., a small number); think oligarchy. An oligonucleotide is a short (i.e., not long and not tiny) synthetic strand of nucleotides.
In other words, an ASO is a short strand of DNA or RNA synthesized for therapeutic purposes to cancel out an undesired nucleotide sequence in someone’s RNA. Unlike CRISPR/Cas9, which changes the original DNA, applying an ASO does not modify the original DNA. CRISPR/Cas13, which is bound to steal the spotlight, is back to modifying the RNA not the DNA.
An elephant’s faithful, one hundred percent
I still meant what I said earlier, with some added nuance:
- Gene silencing via direct injections into the brain or spinal canal might temporarily quiet down some of the toxic protein creation within individual cells. How is that good enough? How toxic is the leftover and future toxic protein? That is not disease eradication in an individual but amelioration at best.
- New research takes decades to not succeed so it can go in another direction, and there are no examples of human gene-silencing therapies in the market today for any genetic neuronal disease (i.e., there is not even an established direction yet).
- In 2017, there are unmet challenges with ASO delivery to the brain and specificity. Years will pass; focus will continue to shift to other trendy techniques (e.g., CRISPR).
- To prevent an adult-onset genetic brain disease, better therapy than what exists in laboratories must be developed and (my guess) then applied starting in early childhood long before symptoms (though the zygotic-blastocystic-embryonic-fetal-newborn stages would be more ideal). Adults with symptoms? Way too late.
- We’re barely scratching the surface of disease amelioration. Maybe after many decades, the theoretical goals of pure gene silencing will be achieved, but then genetic defects such as SCA can and will be passed to offspring even when the parent is not symptomatic, ensuring that the disease is around forever.
I think that focus could be more on disease prevention rather than (inherently) imperfect treatment.
The state of ASOs and SCA3
Company to watch: Ionis Pharmaceuticals.