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MikeHerp posted a topic in Herpes Clinical Trials & VaccinesI'm just thinking out loud here, but the recent study results which were posted, were quite encouraging. This will hopefully be followed up with a research paper or extensive writeup so that we can read the details. But in a nut shell, it appears that Keith Jerome's team at the Hutch Center, was able to edit almost 20 to 30% of latent HSV in mice using endonucleases, if I understood the limited blurb about his recent research correctly. What I like about this is the following: 1. In the space of around 2 years, their lab has been able to improve editing efficiency, from 2%-4% to almost 20% to 30% of latent virus, if I understood the recent blurb about his work correctly. So editing efficiency has been improved by more than 5 to 10 times in the space of 2 years. I wouldn't necessarily extrapolate those numbers going forward, but the point is that, this technology appears to have been significantly improved in a relatively short time. That's intriguing, because even at 2-4% editing, there seemed to be a hint of disruption of replicating HSV virus. It's unclear whether Keith Jerome did a replication study post editing this time as well. If he did, I'd imagine that this level of editing would result in a tangible and measurable disruption in replication. 2. In the past, it has been noted that CRISPR Cas9 has been unable to edit latent virus in non-dividing neurons. But the reasons that were given, were that HSV in its quiescent state in such neurons is a lot harder to access for CRISPR. In the blurb regarding Jerome's recent work, it was also noted that his effort with CRISPR Cas9 was unable to edit latent HSV, which certainly mirrored the previous understanding (though by saying that editing was "less than 1%", it seems to suggest that maybe there was some very very minor editing). That's also consistent with EDITAS recent rabbit corneal HSV study using CRISPR Cas9, which showed that Cas9 couldn't reach the latent HSV (even if it produced significant reduction of symptoms on the cornea). It's pretty clear that CRISPR Cas9, as is, can't touch latent HSV. But I noticed that the reason why Jerome speculated that CRISPR couldn't edit latent HSV well, was that the size of Cas9 was too large to allow for much optimization. I.e., it wasn't necessarily related to the location, but rather size of the editor. If you have been following my comments on here and on my blog, you'll know that I've taken a bit of a glass half empty view of ExcisionBio's efforts regarding HSV. Simply put, while their approach was intriguing and could theoretically stop HSV replication, I had understood from their previous work that their efforts were concentrated around the notion that, they'd seed our body with CRISPRs that would have to continuously edit newly replicating virus while being unable to touch latent virus. Even considering the continuous improvements in CRISPR safety, it just seemed kind of far fetched that the FDA would approve a gene editing treatment any time soon that was centered around CRISPR making endless and continuous DNA edits in our bodies indefinitely. That's understandable. Even very minor off target edits, when piled up over years and decades, might presumably make us very sick or worse. That was my thinking then. But if the issue is more about the size of the editor, as suggested by Jerome, than maybe ExcisionBio's efforts might be on the right track after all. As people who have been following their work know, their intent is to use CasY not Cas9 for HSV2 (though the info provided by ExcisionBio seems a bit scant and sketchy and their website leaves tons to be desired). CasY is smaller than Cas9, so perhaps it could have a chance to edit latent HSV if Jerome's comment is correct. Cas9 which Jerome used in his experiments, seems almost like old tech now, compared to the newly discovered Cas types. That's intriguing because, Jerome did note that Cas9 editing of HSV in vitro, was very high (around 50%), even while it did next to nothing against latent HSV. So that's all very interesting to me. But there are various caveats. Jerome's latest research hasn't been published yet, as far as I know. It's unclear what stumbling blocks might arise in humans relative to mice. One important question is, whether partial editing of some latent HSV would allow for a partial cure, and whether this would remain so going forward. Could the "cured" neurons, be reseeded by active replicating HSV virions again? Would the gene editors need to remain in the cells indefinitely (that, in my view, would make the treatment more questionable from a safety perspective). In his previous work, Jerome noted that the endonucleases persisted in the cells for a prolonged period, which makes me wonder. From the safety perspective, it seems it would be best, if they didn't persist in our bodies and dissipated after editing the latent virus. So some pretty major questions still remain. But this stuff is interesting.