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MikeHerp

GREAT NEWS! Dr. Jerome at Fred Hutch has achieved 50% to 90% elimination of latent HSV in mice

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Inevitablecur3

I agree with all that. I wonder if they could use a defective form of hsv to reach the same neurons? That way it would be the same virus going the same route with meganuclease but unable to replicate in the neurons

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BioHacker
Posted (edited)

It's good that they are doing this, and hopefully it works. It has a hard path to potential approval though, since the technique would need to be proven safe first, which would likely happen first in treating different types of cancer or other high risk / infectious / nerve diseases. It's not a controversy when cancer patients get worse due to experimental treatment, or if they suffer serious side effects - if they were terminal, then it is reasoned that they signed up for that possibility. With a chronic "minor" condition like HSV, those risks don't get taken. So that pushes the timing out, way out, past all the other higher-priority diseases that can be treated with gene editing. Once there is a cure for some other disease using a similar gene editing method, and all you'd need to do is substitute HSV as the target, and all that remained was doing it and testing it, THEN you'd probably be 10-20 years away . . . if you could somehow get funding . . . Of course, someone outside a regulated environment could do it, but with gene editing that would seem pretty risky . . .

Edited by BioHacker

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Cas9
On 4/16/2019 at 2:48 AM, BioHacker said:

It's good that they are doing this, and hopefully it works. It has a hard path to potential approval though, since the technique would need to be proven safe first, which would likely happen first in treating different types of cancer or other high risk / infectious / nerve diseases. It's not a controversy when cancer patients get worse due to experimental treatment, or if they suffer serious side effects - if they were terminal, then it is reasoned that they signed up for that possibility. With a chronic "minor" condition like HSV, those risks don't get taken. So that pushes the timing out, way out, past all the other higher-priority diseases that can be treated with gene editing. Once there is a cure for some other disease using a similar gene editing method, and all you'd need to do is substitute HSV as the target, and all that remained was doing it and testing it, THEN you'd probably be 10-20 years away . . . if you could somehow get funding . . . Of course, someone outside a regulated environment could do it, but with gene editing that would seem pretty risky . . .

Proving its safety should be done just like any other disease; i.e. animal studies followed by phase 1 of human trials. If there were no serious diseases like cancer etc.. to be tested with gene editing, then based on your thinking, Jerome's clinical trials would never happen.

That said, other serious diseases are in fact going to trial.  Editas and CRISPR Therapeutics are a couple of companies that have started or are close to starting clinical trials. In the mean time, Jerome will be working on fixing the issues he's currently encountering. That will probably take at least a few years; it's hard to predict.

Assuming that Editas et al get through phase 1 (the safety phase) without any problems, which is more likely than not, then that will further help Jerome advance to clinical.

Edited by Cas9

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Tired of waiting

CRISPR therapeutics are actually recruiting for sickle cell anemia. so it looks like the technology is being proven pretty quickly. 

 https://sicklecellanemianews.com/2019/02/28/first-patient-enrolled-phase-1-2-trial-ctx001/

 I think in our case, as the nerves need to be targeted, it's going to take time to figure out a delivery mechanism Vs.  proving the editors work?  It seems like Jerome is almost there based on the last video presentation. Please correct me if my interpretation is  not correct,  but it sounded like the gene editors where delivered to where they wanted them to go and they worked as intended, but they did not realize there are other possible locations for the HSV to reside, and that additional delivery methods (to target other nerve groups) are needed to reach the other locations?

Edited by Tired of waiting

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Inevitablecur3

I agree with that. Especially since he’s using meganuclease which as far as I know is less likely to cause off target edits than crispr. I think over the next year or two Jerome’s lab will hone in on more efficient delivery and it could be tested in people within five years. It seems gene editing is moving so fast with new advancements all the time these days :)

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Inevitablecur3

Yea the scg was a new area they mentioned in the video that seemed to harbor less hsv than the tg. They found that different vectors make it to different types of neurons with different efficiency. Now it seems they just have to figure out how to maximize reaching all the neurons. I think if they can go from 2-4% a few years ago to over 50% in the tg and 90% in the scg, they can get to 100%

Edited by Inevitablecur3

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Sadhiker

I'd love to see mice experiments with HSV-2 and using AAV to target the sacral ganglia.  Maybe he already has this data?

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Cas9
1 hour ago, Sadhiker said:

I'd love to see mice experiments with HSV-2 and using AAV to target the sacral ganglia.  Maybe he already has this data?

My question is whether the SCG and the SG (which are ganglions in different locations), are the same neuron types.  If they are then whatever results Jerome encounters regarding the SCG, I would assume applies (in terms of AAV deliverance) to the SG (aka DRG) as well.

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Sadhiker
15 minutes ago, Cas9 said:

My question is whether the SCG and the SG (which are ganglions in different locations), are the same neuron types.  If they are then whatever results Jerome encounters regarding the SCG, I would assume applies (in terms of AAV deliverance) to the SG (aka DRG) as well.

True, and whether the enzymes the AAV contains will cause a mutation in the latent HSV-2 DNA if he infects the mice with HSV-2

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Tired of waiting

Assuming the proper set of AAVs are developed, does anyone have an informed opinion as to the steps needed to human trials. specifically do we need to follow the same dogma used for vaccines, going through mice, guinea pigs, primates then humans?  It seems pretty conclusive the editors work without off target modification being made ( I assume off target means edits not directly related to HSV, otherwise why would I not want HSV eradicated from any location in my body?)  making the intervening animal studies kind of redundant and not adding much to the final implementation of a cure?

 In the other gene editing stories out there I did not see specific steps needed to get to human trials. If I'm recalling correctly the sickle cell study and now clinical trials started around 2015-16 time frame? a pretty short time period?

Without getting too far ahead of the research I think we are pretty close to a cure in the next few years?

Edited by Tired of waiting

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Lost-hope
1 hour ago, Tired of waiting said:

Assuming the proper set of AAVs are developed, does anyone have an informed opinion as to the steps needed to human trials. specifically do we need to follow the same dogma used for vaccines, going through mice, guinea pigs, primates then humans?  It seems pretty conclusive the editors work without off target modification being made ( I assume off target means edits not directly related to HSV, otherwise why would I not want HSV eradicated from any location in my body?)  making the intervening animal studies kind of redundant and not adding much to the final implementation of a cure?

 In the other gene editing stores out there I did not see specific steps needed to get to human trials. If I'm recalling correctly the sickle cell study and now clinical trials started around 2015-16 time frame?   a pretty short time period?

Without getting too far ahead of the research I think we are pretty close to a cure in the nest few years?

Here a good article on how the FDA is dealing with clinical trials with gene therapy 

https://www.nejm.org/doi/full/10.1056/NEJMp1810628

 

In 2017, the FDA approved the first three gene-therapy products for use in the United States.

•the fact that the FDA currently has more than 700 active investigational new drug applications for gene therapies, it seems reasonable to envision a day when gene therapy will be a mainstay of treatment for many diseases.

•the field made a quantum leap forward about 5 years ago with the discovery and development of the CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 gene-editing system.

•researchers have announced the first in vivo clinical trial of genome editing to correct Hunter’s syndrome by means of ZFNs, and CRISPR-Cas9 and TALENs gene-editing approaches are being explored in the clinic for T-cell immunotherapy.

its a long read read but just a few of many points I highlighted 

hope this is helpful 

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Inevitablecur3

It looks like scg and tg are different neuron types and therefore will require different viral vectors to get the meganuclease in them efficiently. I was reading about some viral vectors like lentivirus that can reach up to 90% transfection so I imagine with new vectors being discovered, 100% will be achievable :) just need more time for them to test new and different vector types. I really think if a virus like hsv can get into neurons, researchers will find a way to get all of them out too

Edited by Inevitablecur3

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BioHacker

Yeah, the Bubble Boy treatment is pretty cool, but it's a bone marrow transplant fix (like the one or two patients cured of HIV). If gene editing as treatment for a minor chronic disease (like HSV) ever becomes widespread, it will likely come AFTER that approach has already been in widespread use to treat cancer and life-threatening diseases. The most prestigious research is happening in cancer, HIV, genetic conditions, etc. Researchers who are talented do branch out into diseases of lower priority, maybe because they have a great idea about it, or maybe because they can't get funding in a highly competitive area like cancer or HIV, and they still want to test their theories. It just means that it's lower funding, lower FDA priority, and a slower rate of progress, less media attention, and so more need for self-promotion and media campaigns to attract attention and funding. There is really no other way, to be sure, but it is what it is. 

The most probable way a "functional cure" or therapeutic vax for HSV will get created in the near term is on the cheap - essentially taking a technique developed for cancer vaccines (most likely) and applying to to creating a therapeutic / preventative HSV vaccine.

Technically, they already have cancer vaccines tested in humans (though not approved yet) which are therapeutic against cancer, achieved by triggering some pretty significant interferon response and CD8+ T Cell response (exact same responses needed for HSV).  Of course it's not so simple as to just take a cancer vaccine, mix in some HSV antigens, and presto, you've got a good HSV vaccine . . . But it is ALMOST that simple.  If safe, such an HSV vaccine would likely be at least 60% (and maybe closer to 100%) therapeutic (in terms of symptom / shedding reduction), and highly effective as preventative. The hurdles to having something like that in-hand are much lower than a gene editing treatment - indeed most of the necessary materials are available to researchers already. Of course, it would be great to have both treatment types - gene editing and a vaccine would not be mutually exclusive, indeed, they would likely be complimentary.

 

 

 

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Cas9
52 minutes ago, BioHacker said:

Yeah, the Bubble Boy treatment is pretty cool, but it's a bone marrow transplant fix (like the one or two patients cured of HIV). If gene editing as treatment for a minor chronic disease (like HSV) ever becomes widespread, it will likely come AFTER that approach has already been in widespread use to treat cancer and life-threatening diseases. The most prestigious research is happening in cancer, HIV, genetic conditions, etc. Researchers who are talented do branch out into diseases of lower priority, maybe because they have a great idea about it, or maybe because they can't get funding in a highly competitive area like cancer or HIV, and they still want to test their theories. It just means that it's lower funding, lower FDA priority, and a slower rate of progress, less media attention, and so more need for self-promotion and media campaigns to attract attention and funding. There is really no other way, to be sure, but it is what it is. 

The most probable way a "functional cure" or therapeutic vax for HSV will get created in the near term is on the cheap - essentially taking a technique developed for cancer vaccines (most likely) and applying to to creating a therapeutic / preventative HSV vaccine.

Technically, they already have cancer vaccines tested in humans (though not approved yet) which are therapeutic against cancer, achieved by triggering some pretty significant interferon response and CD8+ T Cell response (exact same responses needed for HSV).  Of course it's not so simple as to just take a cancer vaccine, mix in some HSV antigens, and presto, you've got a good HSV vaccine . . . But it is ALMOST that simple.  If safe, such an HSV vaccine would likely be at least 60% (and maybe closer to 100%) therapeutic (in terms of symptom / shedding reduction), and highly effective as preventative. The hurdles to having something like that in-hand are much lower than a gene editing treatment - indeed most of the necessary materials are available to researchers already. Of course, it would be great to have both treatment types - gene editing and a vaccine would not be mutually exclusive, indeed, they would likely be complimentary.

 

 

 

I don't think you really know what you're talking about, which I've already discussed after your previous comment. You're a bio hacker alright

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Inevitablecur3

Yea a vaccine i think would take much longer than gene editing but that’s just my opinion. 

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MikeHerp
On 4/16/2019 at 3:48 PM, BioHacker said:

It's good that they are doing this, and hopefully it works. It has a hard path to potential approval though, since the technique would need to be proven safe first, which would likely happen first in treating different types of cancer or other high risk / infectious / nerve diseases. It's not a controversy when cancer patients get worse due to experimental treatment, or if they suffer serious side effects - if they were terminal, then it is reasoned that they signed up for that possibility. With a chronic "minor" condition like HSV, those risks don't get taken. So that pushes the timing out, way out, past all the other higher-priority diseases that can be treated with gene editing. Once there is a cure for some other disease using a similar gene editing method, and all you'd need to do is substitute HSV as the target, and all that remained was doing it and testing it, THEN you'd probably be 10-20 years away . . . if you could somehow get funding . . . Of course, someone outside a regulated environment could do it, but with gene editing that would seem pretty risky . . .

I don’t think this is the correct way to think about it. Dr Jerome has noted that they plan to be in human trials in the not too distant future.

Here are some points to consider:

1. You say that HSV is a “minor” condition but that’s 1980s thinking and recent research has veered away from that with a resultong increase  in HSV cure research and funding. Look at the first 10 or 15 minutes of Jerome’s Video and you can understand why. He explains that HSV greatly ups the risk of HIV acquisition. And HIV is implicated in skyrocketing risks for a number of cancers. In one study I read, in Kenya 48% of HIV positive ppl acquired HIV due to HSV (this study is not cited in the Jerome video). That’s not to mention the links being investigated to Alzheimer’s (which are albeit very tentative), neonatal herpes, herpes keratosis. When you put it all together, the disease burden of HSV is quite substantial. HIV, cancer and Alzheimer’s are 3 of the biggest killers in the world, and HSV is implicated in 2 of them, possibly 3. As Jerome noted in a 2016 interview, it’s now recognized that HSV is definitely worth curing. His research is funded with NIH money as well.

2. Meganucleases seem to enjoy a favorable safety profile to CRISPR. They look for a longer base pair match. CRUSPR trials are proceeding, with one started already and many lining up. IfCRISPER can show safety, meganuckeases may be even more safe.

3. FDA has announced that it will look at gene editing treatments liberally, focusing more on after approval safety.  It’s not going to intentionally hold things up. 

There are risks of course, and it will take time. But I think you’re way too pessimistic. There hasn’t actually been any proven instance yet where an animal got cancer from gene editing. 

As mentioned, this is probably not too far away from hunan trials. And once it gets into them, as Cas9 (the poster) explained, safety will be checked through the trials. If it proves fairly safe then it will be deemed safe enough. 

Edited by MikeHerp

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