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(Excision BioTherapeutics) CRISPR Gene Editing Eliminates Herpes Simplex Virus and JC Virus, Demonstrating Feasibility of a Potential Functional Cure

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Hopeful heart

Hi all, 

I was wondering if we can find out what % they are able to achieve in the "in vivo" model. I did a little digging and found some more details for us, although not as much detail as I would like.

https://link.springer.com/article/10.1007%2Fs13365-019-00807-1

  "...Our preliminary results indicate that targeting essential genes of HSV-1 ICP0 and ICP27 drastically decreases their expression levels, leading to suppression of HSV-1 infection. The specificity of our gene mutation/ablation within the HSV-1 genome has been verified by genetic analysis in an in vitro cell culture model. Furthermore, expression of HSV-1 directed Cas9/gRNAs in cells protected them against HSV-1 infection. Finally, our preliminary results using an in vivo approach in a C57BL/6J mouse model suggest a possible reduction of HSV-1 related lesion in mice injected intraperitoneal and intravenous with CRISPR/Cas9-AAV2. In conclusion, our CRISPR/Cas9 approach may be used to develop a novel, specific and efficient therapeutic platform to target the viral genome to treat HSV-1 associated complications. This work was funded by Excision Biotherapeutics."

So I think we don't really know too much about this "possible reduction of HSV-1 related lesion in mice injected intraperitoneal and intravenous with CRISPR/Cas9-AAV2".

 It sounds to me like Dr. Jerome is still in the lead, but I am happy to see some updates from this company as well.

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Cas9
37 minutes ago, Hopeful heart said:

Hi all, 

I was wondering if we can find out what % they are able to achieve in the "in vivo" model. I did a little digging and found some more details for us, although not as much detail as I would like.

https://link.springer.com/article/10.1007%2Fs13365-019-00807-1

  "...Our preliminary results indicate that targeting essential genes of HSV-1 ICP0 and ICP27 drastically decreases their expression levels, leading to suppression of HSV-1 infection. The specificity of our gene mutation/ablation within the HSV-1 genome has been verified by genetic analysis in an in vitro cell culture model. Furthermore, expression of HSV-1 directed Cas9/gRNAs in cells protected them against HSV-1 infection. Finally, our preliminary results using an in vivo approach in a C57BL/6J mouse model suggest a possible reduction of HSV-1 related lesion in mice injected intraperitoneal and intravenous with CRISPR/Cas9-AAV2. In conclusion, our CRISPR/Cas9 approach may be used to develop a novel, specific and efficient therapeutic platform to target the viral genome to treat HSV-1 associated complications. This work was funded by Excision Biotherapeutics."

So I think we don't really know too much about this "possible reduction of HSV-1 related lesion in mice injected intraperitoneal and intravenous with CRISPR/Cas9-AAV2".

 It sounds to me like Dr. Jerome is still in the lead, but I am happy to see some updates from this company as well.

I agree, Dr. Jerome's work is better. I think Excision's goal is to disable the virus from replicating when it tries to replicate. That would require persistence of Cas9 in the cell,if my assessment is correct.

Dr. Jerome's work indicates that he is actually eliminating most of the virus and permanently disabling most of the rest. It's good what Excision is doing so it's certainly not something to dismiss. But it's Dr. Jerome's work that is the best IMO.

As an FYI, Excision's pipeline for clinical trials has moved up twice; they were supposed to start in 2019. Then they bumped it to 2021; and then bumped it again to 2022/2023.

The bottom line is that it's all good news.

 

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vzhe
6 hours ago, Cas9 said:

I agree, Dr. Jerome's work is better. I think Excision's goal is to disable the virus from replicating when it tries to replicate. That would require persistence of Cas9 in the cell,if my assessment is correct.

Dr. Jerome's work indicates that he is actually eliminating most of the virus and permanently disabling most of the rest. It's good what Excision is doing so it's certainly not something to dismiss. But it's Dr. Jerome's work that is the best IMO.

As an FYI, Excision's pipeline for clinical trials has moved up twice; they were supposed to start in 2019. Then they bumped it to 2021; and then bumped it again to 2022/2023.

The bottom line is that it's all good news.

 

Not what they are saying. they are saying they can modify the virus with the Halford mutation icp0 and another inside the cells. Plus they can protect other cells by making it produce the editing proteins prophylactically (which further reduces an outbreak)

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Cas9
6 hours ago, vzhe said:

Not what they are saying. they are saying they can modify the virus with the Halford mutation icp0 and another inside the cells. Plus they can protect other cells by making it produce the editing proteins prophylactically (which further reduces an outbreak)

Not sure what you are disagreeing with.

Yes, they are modifying the virus to prevent it from replicating (i.e. virus is disabled).  If the virus can't replicate it's harmless.
The modification involves targeting ICP0 and ICP27 genes, which is how it is disabled. I assume by "modification", they mean removal of those genes.

Further, having the gene editing tool in the cells would protect the cell from reinfection, and also protect the other neurons that were never infected, from being infected. That's what I meant by "persistence" in my previous comment.

Anyway, that's how I understand it.

 

Here's what they say (bold and underline print is for emphasis, by me):

" Accordingly, we have customized the recently developed gene editing platform, CRISPR/Cas9, to specifically target the HSV-1 genome with the purpose of making indel mutations or removing large segments of the viral DNA sequences which are important for viral replication. Our preliminary results indicate that targeting essential genes of HSV-1 ICP0 and ICP27 drastically decreases their expression levels, leading to suppression of HSV-1 infection. The specificity of our gene mutation/ablation within the HSV-1 genome has been verified by genetic analysis in an in vitro cell culture model. Furthermore, expression of HSV-1 directed Cas9/gRNAs in cells protected them against HSV-1 infection. "

Edited by Cas9

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MikeHerp

This is a good update. Thanks @Franky26.

I'm glad that they are continuing to develop their approach for HSV.  Though, I think @Cas9 is correct that Dr. Jerome's team is ahead of the pack.

It seems these guys are still "inhibiting" the virus, rather than excising it. The articles note that their results led to viral "suppression".  That is promising, but raises some safety concerns, since the gene editors would have to be maintained indefinitely in the body and continue editing every day.  I'm not sure the FDA is quite ready to approve that yet.

Still, the advance here is that they've now managed to do this in animals, not just test tubes as before.  That's the advance and the significance of the update.

I'm going to ask a friend whether he can obtain any paper from this conference.  Copying in @hsv2fighter

As you guys have noted, this is all good.  It highlights the potential of this technology and that its application to target HSV, is obvious to many.  

Meanwhile, it seems pertinent to also share the recent news that an ex-vivo CRISPR editing treatment appears to have cured two people of serious blood disorders, with the edited cells being reintroduced into the body.  It's emphasized that the gene editing itself appeared to have no side effects (the overall treatment did have side effects since it was accompanied by radiation etc. but the gene editing aspect worked like a charm).  Data will continue to be gathered, but this looks good.  

https://www.statnews.com/2019/11/19/first-crispr-treatment-for-blood-diseases-shows-early-benefits/

In a Forbes article on the same news, they did use the "c" word.  Cure.  

I think we are kind of in a good place with the HSV research.  The reality is that, although the HSV is a natural target for DNA editors, it probably won't be the first one targeted.  The next 2-4 years will bring increasing use of gene editing in more serious illnesses and hopefully that will compile an increasingly large set of safety data. That will help smooth the way for the HSV clinical trials.  within the next 2 to 3 years, there will likely be an explosion in gene editing trials and that will help establish the regulatory framework. 

This stuff is just too promising to hold back.  To remove permanent or incurable illnesses, with no noticeable side effects.  It's unprecedented. The Holy Grail of medicine.  No exxageration.  Stuff of magic.  

In fact, i'm excited about this stuff not just curing my HSV, but possibly curing a future cancer or other otherwise terminal illness I might have and possibly extending my life.  

Edited by MikeHerp

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MikeHerp

 

Thought it would be a good time to again remind the subreddit r/herpes community about the fund raiser ^^

 

 

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dont quit!17
On 11/19/2019 at 1:56 AM, vzhe said:

Not what they are saying. they are saying they can modify the virus with the Halford mutation icp0 and another inside the cells. Plus they can protect other cells by making it produce the editing proteins prophylactically (which further reduces an outbreak)

Thoughts on this? Does this have a punchers chance on giving any therepeutic effect for those affected?

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dont quit!17
On 11/19/2019 at 1:56 AM, vzhe said:

 "Plus they can protect other cells by making it produce the editing proteins prophylactically (which further reduces an outbreak)"

I've skimmed through this briefly and didn't see this information but sounds rather interesting. 

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MikeHerp
7 hours ago, dont quit!17 said:

I've skimmed through this briefly and didn't see this information but sounds rather interesting. 

This experimental treatment would stop HSV virus from replicating inside the body and, in the cells where it resides, it would completely protect those cells.

It's unclear whether, as a result shedding would be completely eliminated or simply minimized, but that's the idea.

For example, when Editas Medicine tested, what I think is a similar approach in rabbits to treat ocular keratisis with CRISPR Cas9, they found lesions were reduced by 91%.

https://editasmedicine.com/wp-content/uploads/2018/06/08.pdf

They also found, however, that the treatment didn't touch latent HSV in the nerve ganglion.  So the infection was there, but the gene editors were around and sprang into action when the virus started replicating on the cornea.

Dr. Jerome's method seems more attractive at the moment, because his meganucleases are able to target latent HSV which CRISPR Cas9 can't (so far).  After latent HSV is destroyed, there's no more need for gene editing scissors to linger in the body.  If it can be figured out how to turn them off or deactivate them, or if the body simply degrades them over time, then that's ideal.  They don't have to be there to edit away newly replicating virus because the latent infection, which is the sources of new replication, would be destroyed.

Still, there could be different ways to cut the cake.  If the stuff ExcisionBio is working on can show long term safety and it amounts to a functional cure,, people probably won't care that they still have latent HSV.  

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JHenry
1 hour ago, MikeHerp said:

This experimental treatment would stop HSV virus from replicating inside the body and, in the cells where it resides, it would completely protect those cells.

It's unclear whether, as a result shedding would be completely eliminated or simply minimized, but that's the idea.

For example, when Editas Medicine tested, what I think is a similar approach in rabbits to treat ocular keratisis with CRISPR Cas9, they found lesions were reduced by 91%.

https://editasmedicine.com/wp-content/uploads/2018/06/08.pdf

They also found, however, that the treatment didn't touch latent HSV in the nerve ganglion.  So the infection was there, but the gene editors were around and sprang into action when the virus started replicating on the cornea.

Dr. Jerome's method seems more attractive at the moment, because his meganucleases are able to target latent HSV which CRISPR Cas9 can't (so far).  After latent HSV is destroyed, there's no more need for gene editing scissors to linger in the body.  If it can be figured out how to turn them off or deactivate them, or if the body simply degrades them over time, then that's ideal.  They don't have to be there to edit away newly replicating virus because the latent infection, which is the sources of new replication, would be destroyed.

Still, there could be different ways to cut the cake.  If the stuff ExcisionBio is working on can show long term safety and it amounts to a functional cure,, people probably won't care that they still have latent HSV.  

MikeHerp, this is a little off topic, but you mention “shedding” above and it made me think of a question that rolled through my mind while driving home today.   As a person with GHSV2—is there any value in a person as myself, showering thoroughly before  participating in sexual activity?   While I realize this would not affect shedding in the urinary track, would it possibly reduce exterior shedding?   

This might be a silly, rolling of the eyes question, but maybe a worse question would be the one not asked?   Thanks, Henry.

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MikeHerp
6 hours ago, JHenry said:

MikeHerp, this is a little off topic, but you mention “shedding” above and it made me think of a question that rolled through my mind while driving home today.   As a person with GHSV2—is there any value in a person as myself, showering thoroughly before  participating in sexual activity?   While I realize this would not affect shedding in the urinary track, would it possibly reduce exterior shedding?   

This might be a silly, rolling of the eyes question, but maybe a worse question would be the one not asked?   Thanks, Henry.

It's a fair question.  I'll be very honest with you:

1.  I don't know and I'm not aware of any study which looked at anything similar to that issue.

2.  I have also wondered about the same.  

One thing I wondered is a related topic--whether sex in the shower might lower risk a bit by, possibly washing away shed virus.  I'm not aware of any studies which support that conclusion.  But, at a certain level, it seems it might be logical?

Still, I would not think that the risk reduction is huge. Sex in the shower is definitely not the same as wearing a condom or something.  If there is any lowering of risk, it's probably minor (but could it reduce risk by 10-15%? maybe?).  Just speculating there, but I really don't know.  It certainly can't be recommended as a go to form of protection, or anything like that.  

ps. Thank you always for your huge support for the fund raiser.  we're all in this together. 

 

Edited by MikeHerp

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JHenry
4 hours ago, MikeHerp said:

It's a fair question.  I'll be very honest with you:

1.  I don't know and I'm not aware of any study which looked at anything similar to that issue.

2.  I have also wondered about the same.  

One thing I wondered is a related topic--whether sex in the shower might lower risk a bit by, possibly washing away shed virus.  I'm not aware of any studies which support that conclusion.  But, at a certain level, it seems it might be logical?

Still, I would not think that the risk reduction is huge. Sex in the shower is definitely not the same as wearing a condom or something.  If there is any lowering of risk, it's probably minor (but could it reduce risk by 10-15%? maybe?).  Just speculating there, but I really don't know.  It certainly can't be recommended as a go to form of protection, or anything like that.  

ps. Thank you always for your huge support for the fund raiser.  we're all in this together. 

 

Thank you MH for your prompt response.  I have asked on this site before and my significant other maintains there is minimal risk of transferring my GHSV2 to them orally, citing “rarely, rarely” does that occur, and because they already have oral HSV1, there may be added prevention of transmission.   Would you agree with this?  Thanks again, Henry. 

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MikeHerp
19 minutes ago, JHenry said:

Thank you MH for your prompt response.  I have asked on this site before and my significant other maintains there is minimal risk of transferring my GHSV2 to them orally, citing “rarely, rarely” does that occur, and because they already have oral HSV1, there may be added prevention of transmission.   Would you agree with this?  Thanks again, Henry. 

Yes, with the first part.  GHSV2 rarely transmits to oral.  I think you're pretty safe there as long as your partner has a relatively healthy immune system.  I'm not aware of any exact stats, but I have read that 95% of HSV2 infections are genital.  That, of course, doesn't speak to the chance of transmitting it, but it does suggest that GHSV2 transmissions to oral are pretty rare.  If your partner has that attitude, I'd definitely run with it and not really feel any hesitance about that.

However, the second part I think is not really proven.  Having HSV1 doesn't really protect against HSV2.  On the other hand, HSV2 does seem to protect against HSV1 however so you don't have to worry too much about your partner transmitting their oral HSV1 to your genitals.  

I don't have any links to this off hand, but I'm pretty sure about it.  I've read it before.

But again, to summarize, you're both very likely to be fine if the lucky lady plays the skin flute on you (or lucky man, as the case may be).

 

Edited by MikeHerp

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JHenry
1 hour ago, MikeHerp said:

Yes, with the first part.  GHSV2 rarely transmits to oral.  I think you're pretty safe there as long as your partner has a relatively healthy immune system.  I'm not aware of any exact stats, but I have read that 95% of HSV2 infections are genital.  That, of course, doesn't speak to the chance of transmitting it, but it does suggest that GHSV2 transmissions to oral are pretty rare.  If your partner has that attitude, I'd definitely run with it and not really feel any hesitance about that.

However, the second part I think is not really proven.  Having HSV1 doesn't really protect against HSV2.  On the other hand, HSV2 does seem to protect against HSV1 however so you don't have to worry too much about your partner transmitting their oral HSV1 to your genitals.  

I don't have any links to this off hand, but I'm pretty sure about it.  I've read it before.

But again, to summarize, you're both very likely to be fine if the lucky lady plays the skin flute on you (or lucky man, as the case may be).

 

LOL, thats funny, thanks!   Just for the asking,  If the partner has oral HSV1,  would that grant any protection against transmission of GHSV2 to them, below the belt?   A bit redundant, with a twist.  Sometimes I feel talking about Herpes and asking questions is akin to playing with a Rubrics Cube.   Thanks again.  Henry. 

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JHenry

If HSV2 is a “reluctant” lodger orally, does it stand to reason it would likely be prone to fewer, less frequent outbreaks?  It occurred to me, if an individual already has oral, speaking objectively here, other than via testing—how would they know if an occurrence was the result of HSV1 or 2?  

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MikeHerp
14 minutes ago, JHenry said:

If HSV2 is a “reluctant” lodger orally, does it stand to reason it would likely be prone to fewer, less frequent outbreaks?  It occurred to me, if an individual already has oral, speaking objectively here, other than via testing—how would they know if an occurrence was the result of HSV1 or 2?  

From what I have read, oral HSV2 almost never has more than 1 outbreak.  And it rarely sheds, if at all.

If you have an oral outbreak while having HSV1 and 2, it's almost certainly HSV1.  

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thatsmycat
15 hours ago, MikeHerp said:

Yes, with the first part.  GHSV2 rarely transmits to oral.  I think you're pretty safe there as long as your partner has a relatively healthy immune system.  I'm not aware of any exact stats, but I have read that 95% of HSV2 infections are genital.  That, of course, doesn't speak to the chance of transmitting it, but it does suggest that GHSV2 transmissions to oral are pretty rare.  If your partner has that attitude, I'd definitely run with it and not really feel any hesitance about that.

However, the second part I think is not really proven.  Having HSV1 doesn't really protect against HSV2.  On the other hand, HSV2 does seem to protect against HSV1 however so you don't have to worry too much about your partner transmitting their oral HSV1 to your genitals.  

I don't have any links to this off hand, but I'm pretty sure about it.  I've read it before.

But again, to summarize, you're both very likely to be fine if the lucky lady plays the skin flute on you (or lucky man, as the case may be).

 

 

I would have to disagree with you on this. I have HSV2 on my mouth and I get outbreaks often. The person who gave it to me also had oral HSV2 and would have outbreaks every couple weeks. Also this Squarex newspost cites the prevalence of oral HSV2. They did not cite any primary literature but it sounds about right. 

https://www.prnewswire.com/news-releases/squarex-announces-positive-results-from-completed-phase-2-study-of-sqx770-in-the-prevention-of-recurrent-herpes-labialis-300896065.html

"Herpes labialis is a common condition characterized by blisters or erosions on the lips and skin around the mouth and nose. Most cases are caused by herpes simplex virus type 1 (HSV-1), but 10-15% of cases are caused by HSV-2 with this percentage reportedly increasing. "

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MikeHerp

Here are some studies I have found on this:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1744863/

Among people with HSV2: Of 1388 people meeting the entry criteria, 44 (3.2%) had HSV-2 isolated at least once from their mouths.  I.e., pretty rare. 

Regarding shedding: " Oral HSV-2 was found less frequently than oral HSV-1 (0.06% v 1%, p<0.001) in people with HSV-1 and HSV-2 antibody, and less frequently than genital HSV-2 (0.09% v 7%, p<0.001)."

0.06% vs. 1%. 0.09% vs. 7%.  That's not just less frequently, that's literally hundreds of times less frequently.  

Same study:

https://sti.bmj.com/content/80/4/272

"Conclusions: Oral reactivation of HSV-2 as defined by viral isolation is uncommon and usually occurs in the setting of first episode of genital HSV-2 or during genital recurrence of HSV-2."

In other words, oral HSV2 activation is uncommon and barely sheds outside of first episode of HSV2.

May I ask, do you have HIV infection or immune suppression?  How weer you diagnosed with oral HSV2

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