This is a cool idea for a possible cure of HIV, and it's great to see researchers trying it out. But from what I heard, CRISPR is quite ineffective: when you want to do gene edits with it, you often do it to cell cultures, then keep only those cells where it actually worked. CRISPR does the cutting only, and you rely on cell repair mechanisms to mend the parts together again: they can be mended in any way.
Also, the reservoir that makes HIV so tricky is in immune cells that are in a sleep state and only wake up every now and then: can the viral vector reach those?
Also important quote from the paper:
> The study was not designed to test the effect on the intact viral reservoir as EBT-001 was given when the viral reservoir was not stable and there was still active viral replication. Additionally, as animals were maintained on ART, we did not test the ability of EBT-001 to extend time to viral rebound or eliminate viral reactivation after an analytical treatment interruption.
I think yes from the article? The whole point of this therapy is to eliminate latent HIV from dormant cells that traditional small molecule retroviral therapy can't access.
> CRISPR does the cutting only, and you rely on cell repair mechanisms to mend the parts together again
But in this case, all we need is the cutting right because we don't care if the HIV survives the interaction.
That’s always a concern with HIV regardless of the treatment. Most therapies include several mechanisms to reduce the probability of adaptation significantly.
You are out of date. CRISPR is extremely effective in live patients, usually packaged in a virus or lipid nano particle.
While CRISPR is often used in cultured cells (eg for CAR T therapies) there are CRISPR therapeutics in live human patients today in phase 3 trials for sickle cell disease (among other indications).
The phase 3 trials you mention were probably for exa-cel, a therapy that involves removing the cells from the patient, editing them with CRISPR in the dish. Meanwhile you do myeloablation of the patient, aka destroy their bone marrow, then put in the repaired cells. The key here is: the application of CRISPR happens outside of the patient.
> Approximately 80% of the alleles at this locus were modified, with no evidence of off-target editing. After undergoing myeloablation, two patients - one with TDT and the other with SCD - received autologous CD34+ cells edited with CRISPR-Cas9 targeting the same BCL11A enhancer.
Similar (not the same) things have already been done multiple times for HIV patients who had to have their bone marrow destroyed for other reasons, generally leukemia (Düsseldorf Patient, Geneva Patient, London Patient, etc). They received transplants from donors that had mutations in CCR5, which prevents HIV. But you can't cure 40 million people living with HIV that way.
This therapy is extremely involved, expensive, and it also impacts the health of the patient (e.g. their entire immune memory is reset, they have to redo all their vaccinations). You don't destroy the bone marrow of someone due to no reason. Them requiring regular blood transfusions is a good reason, but them having to take antiretroviral drugs once per day is generally not seen as one.
The paper of this thread is about a single injection that does these CRISPR edits while inside the patient, without involving destruction of the bone marrow.
Not many viruses can stay dormant. They need to be adapted for that. A classic example is the herpes virus, that has special proteins that regulate its expression.
HIV is a retrovirus, it inserts itself into the hosts's genome, making dormancy easier.
Latent HIV infectious reservoir are especially stealthy, when viral titers are undetectable in the blood, its hiding behind the blood brain barrier.
"The major reservoirs for HIV in the CNS are in the microglia, perivascular macrophages, and to a lesser extent, astrocytes"
https://pubmed.ncbi.nlm.nih.gov/27873219/
Wow this is super interesting! I’m just a layperson, but what’s interesting to me is that this seems distinct from past therapeutic uses of CRISPR that I am familiar with like CAR-T.
In CAR-T, we use CRISPR to modify immune cells so they know how to attack the target (cancer).
But in this approach, it seems more like we have created a new virus that uses CRISPR to directly edit and damage the SIV virus, which is nuts.
Most news is source from places that are not reputable, with a lot of the publishings recently going under extreme scrutiny the best a person can do is look at any CRISPR advancement with optimism and wait patiently till all collective facts are in.Just in case anyone gets too excited.
The source here is the journal Nature,[0] which is one of the two most prestigious scientific journals in the world (together with Science).
That being said, Nature publishes the highest impact papers, which often turn out to be wrong (or overstated). Still, this isn't some random news source trying to report about science.
0. I realized after commenting here that the journal is Gene Therapy, which is part of the Nature Publishing Group, rather than Nature itself.
Whilst historically those publications enjoy such a reputation you can find a body important retractions and delayed retractions in both journals. The Spectator magazine of 12th of August this year has some recent specifics. Titles used to almost regularly pass through phases of better and worse administration it doesn't mean that the name is ruined when things go wrong, but the purpose of publication has never been to establish unassailable truths something that I am sure that every editor concurs with for legal practical moral and social reasons.
Certainly don't want to be that person. I just want people to curb their enthusiam a lot of stuff by colleges especially research is getting torn apart. Most often people in the field were pressured for results to keep receiving funding which is problematic. It itself has that startup momentum where even if the science isn't perfect they'll gamble it and fix it later after the investments. We still do not know the long term effects of COVID vaccines using the expiremental design. We don't know what sort of diseases are introduced after gene editing.
> We still do not know the long term effects of COVID vaccines using the expiremental design.
First, the CoVID vaccines have been more extensively studied than most other vaccines by this point.
Second, "long-term effects of vaccines" reveals an unfamiliarity with how vaccines work. Vaccine side-effects show up quickly, within weeks at most. After months or years, the only thing left of the vaccine in your body is the immune system memory it induced.
Read the Inactivated mouse brain–derived JE vaccine section.
These reactions seem to be more about mouse brain prions, and there was a rare case of (unproven!!) issues a year out, which were cited during discussions about forced discontinuation.
I can't seem to find that, but anyhow, the > 1 month issues are well accepted.
I am saying you need to be mid. Know the risks and the consequences. Long term side effects can result in anything. mRNA itself has been used for vaccines since 2013. We learned how mRNA works in 1960, this is messenger ribonucleic acid. Vaccines through it were proposedd in the 90s, but development of vaccines didn't start till late 2000s. Some long term side effects of COVID vaccines are linking to an increased risk for uterine fibroids. The discovery of potential problems is ongoing. But it was a great achievement for rabies, considering the other options were not great.
Because whenever someone has a really big result, they try to publish it in Nature or Science.
By their very nature, big results are more likely to be wrong than small, incremental results. The main reason why Nature is prestigious is because getting published there means the scientific reviewers and editors think your result is really important.
Is this supposed to be a cure or a treatment? It seems like to be a cure it would have to catch every instance of the virus in the body, which seems like it would be hard
Is "eliminates" the right word here? My reading of the article abstract is that the treatment kills virus particles and in higher doses, the macaques showed increased white blood counts. But that's not to say that the monkeys are cured. Maybe "reduces viral load" might be a better phrasing?
It's quite possible that "eliminates" is not the right word, but I had a difficult time fitting all the relevant information into the title while remaining under HN's 80-character limit. The phrase that I would have preferred to use was "effectively removes".
"Approximately 9" participants seems surprisingly low. Although to be honest, if I were infected with HIV and on HAART, I think I would find it hard to justify to myself an experimental gene therapy when HAART is already pretty darn effective.
But maybe I would... my understanding is the impact on life expectancy is still there once you get older. My guess is the constraint is more regulatory/clinical than lack of demand.
"to evaluate the safety, tolerability, and preliminary efficacy of EBT-101"
The primary question is "will anyone die or have extreme negative side effects". They run the study small in this phase because it might kill or seriously harm the entire study population.
Once they know that nothing extremely bad happened, they'll try on bigger populations.
That's (phase 2) the preliminary efficacy bit mentioned. But it's not really looking for a great, high quality signal: just some evidence that some indicators move in patients and not necessarily even statistical significance before moving to a phase 3 trial designed to measure benefit.
They expect a big enough effect on the virus to be able to measure it in this tiny population.
9 seems adequate to get some kind of statistical significance from the results. Additionally if this somehow has a very high mortality rate, due to unseen consequences, 9 is a lower number than say, 300.
In reality though, running medical trials is hugely expensive, the FDA requires all kinds of procedural documentation, as well as documentation of software code etc.
No suggestion of "forged ethical review documents and misled doctors into unknowingly implanting gene-edited embryos" in this case, either.
> The field of gene editing will carry the hashtag #CRISPRbabies in the mind of the public for a period longer than He's sentence, and that is an additional crime he committed but was not formally charged with," says Fyodor Urnov, a CRISPR researcher at University of California, Berkeley
The intent of that scientist was to purportedly edit genes that made some people susceptible to some HIV infections so that the virus won't be acquired.
The intent in the OP is to remove virus genetics from infected cells' genomes with an existing HIV infection.
Also, the reservoir that makes HIV so tricky is in immune cells that are in a sleep state and only wake up every now and then: can the viral vector reach those?
Also important quote from the paper:
> The study was not designed to test the effect on the intact viral reservoir as EBT-001 was given when the viral reservoir was not stable and there was still active viral replication. Additionally, as animals were maintained on ART, we did not test the ability of EBT-001 to extend time to viral rebound or eliminate viral reactivation after an analytical treatment interruption.