HIV cured in animal models for first time by combined ART/CRISPR therapy

#1

This is the first time a treatment has cured HIV by eliminating the viral DNA from the genome of living animals.

There is no direct application of this specifically as PFS is not a virus, however it shows how exceptionally fast-moving this genomic level technology is, that already this has the potential to be a translatable cure for a disease that until the advent of these tools could only be suppressed. Just posting in case anyone else is interested.

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice

…we employed a broad range of highly sensitive tests to evaluate HIV-1 elimination by LASER ART and AAV9-delivered CRISPR-Cas9 treatments. These included viral gene amplification, flow cytometry, adoptive viral transfers, on target and off target assays, and measures of viral rebound to demonstrate that combination therapies can safely lead to the elimination of HIV-1 infection. Results demonstrated that eradication of replication-competent HIV-1 present in infectious cell and tissue sites of infected animals can be achieved. Although reappearance of viremia in humans can be delayed, rebound occurs on average 2 to 4 weeks after ART interruption and 5 to 11 days in humanized mice. Despite the vigorous treatments offered, there was no evidence of outward untoward effects of any therapies including the persistence of human adult lymphocytes in mouse plasma and tissue. As such, these proof-of-concept results offer readily defined and realistic pathways toward strategies for HIV-1 elimination.

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#2

Wow! very interesting article for us!
Science is developing very fast and more fast.
and now survey is almost done by pfs suffers about 100 people.
i believe in the future, we can get a happy life with healthy mind and body.

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#3

After reading what Awor and OP have had to say about CRISPR in the past, ive never doubted that we could potentially benefit from CRISPR in the near future.

This just adds further reassurance.

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#4

On a purely theoretical level, do you think that the use of CRISPR for PFS would be simpler or more complex than for HIV?

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#5

@axolotl @awor would love to know your thoughts on this question from @Sawproblemo

#6

So i’m just answering this to the best of my knowledge, until Ax/Awor chime in with their thoughts.

What we’ve seen with CRISPR the past couple of years is that it’s being refined to be applicable to more and more cases (types of cells, types of modifications, etc), with fewer side effects.

For example, while CRISPR initially could edit an organism’s genome, it couldn’t do so with an organism’s epigenome. Initially it couldn’t work with neurons, but they’ve adapted it so that it can now and that means it could have applications in diseases that are primarily neurological in origin. So the technology to make the necessary genetic or epigenetic adjustments appears to be coming along nicely, which is great news.

What we don’t have at the moment though, is what we need to change. It just comes down to finding out what’s wrong with our genome/epigenome, and as for whether that’s harder or easier than curing HIV, I wouldn’t know.

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#7

The basic technology and it’s challenges remains the same, no matter what the underlying disease being treated. Currently, such challenges include safety and efficacy of delivery methods (i.e. how is CRISPR/Cas9 delivered into cells), as wells as concerns over potential damage to DNA done by Cas9, which could for example result in cancer.

In any case, if we want to do gene editing with CRISPR, we obviously need to precisely know which genes to edit. Only one study has comprehensively looked into this so far, in the sense of analyzing full genome gene expression. This is the Baylor study, which unfortunately has yet to publish. But supposing they do, and find many deregulated genes, we still need to understand what is cause and what is effect, so we can target the right one(s).

Even though I am hopeful regarding this technology, I am not regarding our current approach of working with institutions the way we are, where the scientists are sometimes doing whatever they feel like doing, and/or whenever they feel like it. As I wrote before, we need to start working with these people on a contract research basis, where we tell them what to do and give them deadlines. If they don’t deliver as agreed, then we don’t fully pay and fire them. For me, the direction and approach would be very clear, but some would probably not agree with that, which makes the “we tell them what to do” part difficult. Another hurdle is the substantial funding required for this approach. In any case, if you are reading this, and have at 7 digit sum to invest into curing PFS, drop me a line. Even a mid range 6 digit sum would be a good start :slight_smile:

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Baylor study delayed again
#8

I suppose this is why we need to try to prove to the best of our abilities that PFS, PSSD, and PAS are all much the same?

It’s frustrating that even if we identify genes which are dis-regulated, we still have to prove cause and effect (I can’t foresee how this can be done easily) and then we are rather impotent to do anything about it regardless.

So for all of you out there begging and pleading for the Baylor study to be released… it won’t provide an immediate panacea by any measure.

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#9

First paragraph: Exactly. See Awor’s post here; Androgen receptor (AR) overexpression and sensitivity to hormones reversed by epigenetic therapy that restores Purα to a transcriptional repressor complex (RC) of AR deregulated in hormone refractory prostate cancer (HRPC) | Journal of Clinical Oncology. I am not sure whether this would allow us to call the shots as I expect that we will need scientists who know how to file for such funds, but without huge funding it will be even more extremely difficult to solve this highly complex problem. Right now we are like a random Internet community trying to land a human on Mars.

Second paragraph: Absolutely. This is an extremely difficult problem. Molecular biology is extremely complex and there is a lot of stuff that is still largely in the dark. This is multiplied by the fact that our condition clearly affects each individual differently in different tissues to a different degree. If at least the symptoms were limited and the same… . And even if we figure all this out, there is no guarantee that we can do something about it. That’s the reality, really. But you never know, maybe we get lucky and can identify one or a few mechanisms that would affect the whole condition. Afterall, it took just one compound to cause all of this. Maybe, science makes a breakthrough and things snowball. We will probably need some lucky breaks on the way, but we also need to be prepared to profit from them. Hence, irregardless of how difficult all of this appears, we need to put in the work to have any chance at all.

Third paragraph: No, it probably won’t. But hopefully, it will clearly demonstrate changes in gene expression compared to controls and elucidate on the epigenetic changes responsible for these changes in gene expression. It’s will hopefully make clear that this problem has broad physiologically consequenes that are not “in our head” and not simply caused by neurosteroids.

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#10

Why don’t we fund you @Awor instead of the foundation? I think instead of putting all our eggs in one basket, hoping we’ll get the right scientific team, in the right country with the right ethics.

I think we should be focusing on the people who have a clear vision of what we should be doing in order to gain a further understanding of this disease, that’ll hopefully lead to potential treatments faster.

I for one would be up for you leading a study since you’ve pretty much been the only person who’s made a dent in this mess over the last decade, without you we’d probably be nowhere today, you and Axolotl for that matter.
It sounds so simple too, just a bit of money… I know money doesn’t lead to happiness or make everything better, but in our case 1 million could potentially be revolutionary. There’s so many people in the world that 1 million is pocket change to.

Surely if we have a genome study and actual proof for the masses to see, a good heartbreaking Gofundme campaign, with written and video accounts of people’s suffering would catch mainstream attention and the hearts of the public?

People get money for MUCH less these days.

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#11

Thanks for your kind words @Devolution. You may be aware that I am one of the three original founding members of the PFS Foundation, so there is no conflict of interest here. Besides a lack of funding, an even bigger problem is the lack of good research opportunities. The Baylor study was designed to find out what is deregulated in our cells so we know what to focus on. In the absence of their results, we unfortunately are poking around in the dark. Sure, Roberto Melcangi has shown some interesting effects such as deregulated neurosteroids, methylated 5ar2 and even an impact on the gut. But to move to the next step, we need to understand what mechanism is causing these. Even AR overexpression is just a result of something which is deregulated, the question is what, or rather which genes.

As Baylor seems to be stuck for the moment, we need a different approach while waiting. @axolotl and I are working on a new angle, with new people. @Dubya_B is going to start working on the analysis of our 23andMe data soon. Please submit your if you can, and have not already done so. In short, we will keep on moving, despite the many hurdles that are thrown at us. I guess that is the destiny of us “PFS” patients, never give up.

Lol, that’s a nice analogy. But consider the following: Up to not so long ago, space exploration was reserved to the likes of NASA. These days, private enterprises have taken over. If you extrapolate this trend, we might eventually reach the point where a random internet community will actually succeed in landing someone on Mars… :slightly_smiling_face: …or in our case: advance science in a way that not even scientists managed to do before. While scientists are highly trained specialists, usually in a very tightly focused area of expertise, they have one huge disadvantage in our case:

“To a man with a hammer, everything looks like a nail.”
(The Law of the Instrument)

The law of the instrument, otherwise known as Maslow’s hammer is a cognitive bias that involves an over-reliance on a familiar tool. As Abraham Maslow said in 1966, “I suppose it is tempting, if the only tool you have is a hammer, to treat everything as if it were a nail.”

Our advantage is, that we are in a position to look at this problem from a very broad perspective, something which scientists rarely do (and are capable of). Once we start seeing the true outline of this problem, we can then start to focus on the correct scope. To help us with this, please take the survey.

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#12

Seems like Baylor is a case of doing something whenever they feel like it. :smiley:

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#13

An interesting grant proposal to design custom nucleases that received NIH funding:

Engineering epigenetic therapy for sickle cell disease

…and a resulting publication:

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#14

sorry my comprehension is bad.

did they achieve what they wanted to?

the reverse of this can be directly applicable towards us (potentially)?

#15

Well, they certainly didn’t create a targeted epigenetic therapy to activate the y-globin gene, but they did achieve targeted methylation of mammalian cells in-vitro.

the reverse of this can be directly applicable towards us (potentially)?

If you mean “can we potentially turn on a gene(s) involved in this syndrome with a similar technology, once we have some targets in mind?”, then yes.

Axolotl posted a study last year where a team reports successfully editing the epigenome of mice:

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#16

so this means that as soon as we discover the exact genes that are silenced, we can start treatment experiments with this tech?

#17

This is still in development. So even if we knew what targets to treat, this would not be readily available for us and certainly not be safe. It will take more animal trials and later human trials to be refined. But it is certainly an encouraging topic that our guys have an eye on.

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#18

I wouldn’t lose hope that this means we may have to wait years upon years for relief. At least for neurological symptoms we have Allopregnanolone analogues (eg. Sage 217) which are due to be released within two years. So perhaps it could make the wait until we have a proven genetic-level treatment more tolerable.

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