So how does Cas12a2 mitigate off-target effects?

If it were to work, gene therapy as-is would be possible. Which it is not, not even for those overpriced therapies. I have no doubt that sooner or later it will happen, as the problem space is finite, not infinite, but I simply don't see the correlation here.

> The implications of Cas12a2 on undruggable conditions that exhibit known driver mutation profiles is profound.

So what does this change exactly? Humans defined it as "undruggable conditions". You can reason this is an improvement, but I still see it in failure-territory. If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.

> I am a layperson in this field (I'm a SWE, not in biotech), but I am happy to answer questions.

How does "answering questions" offset the technology being inferior right now?

> So how does Cas12a2 mitigate off-target effects?

Others in this thread may be able to give a better analogy, but I'll try:

Cas9 is like open heart surgery on millions of cells all at once. We know the specific outcome we want - a surgical replacement of a sliver of a sequence - but just like open heart surgery, it's an inexact operation. Cas9 tolerates mismatches which categorically allows off-target matching. It also operates on DNA, so any off-target effects reprogram the cell's primary source code.

We want the Cas9 "patient" cell to survive.

In contrast, Cas12a2 is key-locked self-destruction switch. It targets single-stranded RNA transcripts with a specific guide protein. So the specificity is two-fold: the guide protein doesn't tolerate mismatches, and its operating on a _downstream byproduct_ of the DNA. When the key (guide protein) matches, it unleashes total destruction within the cell.

We want the Cas12a2 "patient" cell to die.

> If it were to work, gene therapy would be an accurate - and affordable - technique. Which it is not right now.

Correct on the first point. If it were to work, gene therapy could be more common. I do not know how to make it affordable, yet. In the models I've built to commercialize this I estimate a Cas12a2 treatment would cost approximately as much as a bone marrow transplant.

> How does "answering questions" offset the technology being inferior right now?

In fairness, asking and seeking answers to questions is all I have right now. There is no cure to my disease so the upside - no matter how futile you may perceive it to be - to me, is infinite.

If I can solve it I may get a few more years with my daughter. If I can't, I can show her how to live fighting for an answer that may never come.

You're not wrong, you and I just have different perspectives on the upside.