"The other problem is with viral vector based gene therapy is you can’t have it again. You develop antibodies which prevent it from working again, and it could
cause a dangerous immune response."
Just wondering - would it make sense to immune-suppress the patient for a short period of administering of the viral-based therapy.
And as they describe that most gene therapies affect only extra-nuclear DNA, and thus have no permanent effect, wouldn't mRNA work better then in such cases - naturally the tech wasn't there 10+ years ago, yet today thanks to COVID it is here.
Why does the Wikipedia page treat this as a publicly available treatment when it is still undergoing trials?
scoot · 18m ago
That seems very expensive for assisted suicide
snitty · 2h ago
I've been working on a piece about how humans effectively have hardened firmware, and gene therapies need to do A LOT to try to get around the various defenses our bodies evolved. I should probably finish that article...
mattigames · 1h ago
If the institutions of science and technology lasted thousands of years evolution would prefer people with the less hardened firmware, as in, the ones to survive and pass their genes would be the ones with the most "hackable" genes.
klipklop · 1h ago
If "your" genes can be so easily modified (down the line by your children doing gene therapies) there is nothing you are really passing on. In fact you are doing the exact opposite. The best way to pass your genes on is to have them hardened, like they already are and stop any gene editing competition before it begins ;-).
barbazoo · 1h ago
Are we still talking egg and sperm in a human body and everybody consenting? In that case, how would having hackable genes improve your chances of survival? If that was a dating app filter maybe.
hamandcheese · 1h ago
If your body doesn't reject gene therapy, you might live longer and reproduce more.
barbazoo · 1h ago
I can see that now, thank you.
catlikesshrimp · 1h ago
Imagine all humans have homogeneous advantageous genetic material. We are all healthy and handsome. And then something random targets one or more of such advantageous genes and we are all wiped because we are very homogeneous.
That happens to anything recombinant we produce: crops, cattle, bacteria. That even applies to dog breeds.
"Advantageous" changes as the environment changes. Being a large long lived strong dinosaur is advantageous until meteorite? Then being a small mammal is advantageous. A population explosion of locusts ravages all plants successfully, until a fungus infects and kills almost all, thankfully for locusts some of them which were not "the best" survived that one infection.
mattigames · 1h ago
Like covid wiped us all right? A deep understanding of our genes means we are more likely to quickly create successful defenses against future hostile organisms, again, the most "hackable" specimens, those in which we could accurately predict the effects of our changes in their genes (including its interactions with virus and vaccines).
And the same homogeneity means that developing a defense for any future hostile organism is much more straightforward, just like e.g. developing software that works on windows is much easier than developing software that works on windows, Linux and mac.
efitz · 1h ago
Not necessarily, because (1) the “wild” viruses would still exist and evolve, competing with treatments and maybe learning to leverage them, and (2) bad people use science too.
cyanydeez · 1h ago
yah what? This is like the CIA arguing for insecure algorithms so they can spy on enemies.
Think again about your statement, what you're saying is the fitest is the easiest to manipulate? Thats just mindboggling bad, cause you'd also be a honey pot for all the other bacteria and viruses out there.
mattigames · 1h ago
Easiest to manipulate by humans, not necessarily by virus and bacteria, believe it or not virus and bacteria don't think the same way than us; there may an overlap but is likely not a full overlap.
cyanydeez · 1h ago
Ok, so you want the CIA only backdoor?
cyanydeez · 1h ago
Imagine if random DNA really could just float in and out of the blood streams genetics? We'd be constantly battling random protein production and weird abnormal stuff.
simmerup · 2h ago
Damn, gene therapy is so promising too
barbarr · 2h ago
The issue was not the gene therapy itself, but the delivery mechanism. They used a virus to administer the gene therapy, and this virus (like most bloodstream impurities) aggregates in the liver. At low doses this is fine, but at high doses, your body's immune response will be laser-focused on the liver, and you die from the side effects of this response.
wiz21c · 2h ago
if it's so obvious that this is going to produce these side effects, then why on earth did they gamble ?
(because, it definitely look like gambling, like "investors are behind us right now, so we have the money to do it, so let's do it before money runs out")
amelius · 2h ago
Could hemodialysis prevent this?
EA-3167 · 2h ago
Yes, dialysis is surprisingly good at filtering out viral particles, but... that's not desirable in this case. After all these viruses are carrying the therapeutic payload, if you filter them out then you might as well not introduce them in the first place.
amelius · 1h ago
Ok, I was thinking more of injecting viruses upstream, and filtering them out downstream (preventing them from entering the liver in the first place). Maybe you could even recycle them.
actionfromafar · 1h ago
But maybe as treatment if liver problems are detected?
EA-3167 · 1h ago
I suppose it's possible at that point, possibly to try and stem the process. The question is just how rapidly this condition emerges, and I suspect (although this is just a suspicion) that the time between onset and a severe reaction is fairly brief. Mostly though the problem is that this is a really complex, whole immune system reaction that's triggered by the AAV in the liver, but simply removing the intial cause probably wouldn't stop the cascade.
I took a look at some of the aftermath reports (i.e. https://pmc.ncbi.nlm.nih.gov/articles/PMC10638066/ and some others) which get into specific details about the course of treatment in several patients who died from this complication. The through-line is an aggressive use of several immune suppressing and modulating therapies to calm the cascade.
I have to admit I can't find any specific discussion about dialysis in that context, so I can only assume that removal of the viral particles would be a case of closing the barn door after the horse escaped.
bgnn · 38m ago
Yeah I was suspecting they would do the treatment with immunosuppressants. Immune response is an unpredictable killer.
khazhoux · 1h ago
I imagine if these deaths could have been prevented by this one-line HN comment, they would have thought of it.
Maybe a better phrasing of your question would be:
> Why is hemodialysis ineffective for this?
goda90 · 56m ago
Hacker News Guidelines > "Be kind. Don't be snarky. Converse curiously; don't cross-examine. Edit out swipes."
I'm guessing they were looking for preferential delivery to certain cell types, and AAVs just happened to have best profile for those. If anything, LNPs might aggregate in the liver even more than AAVs, which can lead to even worse hepatotoxicity if an immune response happens.
sampl3username · 2h ago
I thought lipid nanoparticles were less prone to generate a immune reaction.
snitty · 2h ago
This gene therapy involves a gene called dystrophin, which is one of if not the largest gene in the human genome. Sarepta is actually using a version called microdystrophin, which is a truncated version. It still barely fits into AAV.
Reasons to use AAV: they're going for sustained production of the therapeutic gene, and AAVs are better at doing that than LNPs. LNPs were used in the mRNA COVID vaccine, because they're great at transient production.
To get stable production from an LNP you'd likely have to integrate into the genome, which risks cancer from disrupting oncogenes. You'd also need to package the therapeutic gene with a mechanism of integrating into the genome, like recombinase.
ceejayoz · 2h ago
Probably because the HHS secretary is vehemently opposed to lipid nanoparticles.
> National Institutes of Health officials have urged scientists to remove all references to mRNA vaccine technology from their grant applications, two researchers said, in a move that signaled the agency might abandon a promising field of medical research.
SoftTalker · 2h ago
They've been working on this for years. It's not anything to do with the current administration.
downrightmike · 2h ago
Yeah, if not for Germany, the covid vax wouldn't have been unreachable.
fsckboy · 2h ago
the paywall really cuts down on the readability of this story. a quick google showed plenty of news stories though, their shareprice dropped 40% on the market today.
I'd be curious what the numbers are for the "good" that this therapy does; is there any way that this therapy is still "worth it" at any scale? but I know little about this area so that's a fairly naive question.
mandevil · 1h ago
The answer is, the therapy does not improve much. It was controversial when it was approved, because the Phase III clinical trial failed to show statistically significant improvement- lots of people in the FDA advocated against approving the drug (even without knowledge of these rare fatal side effects) but were overruled by Peter Marks, head of the the biologics for the FDA under Biden.
It seems to me to be similar to the approval of the three Alzheimer's drugs which don't really show improvement either- it seems like over the past decade the FDA has wanted to approve drugs that might work for diseases where there was no treatment at all (while saying things "delivering hope"). And it's not gone well, and has not been a good idea.
Thoughts from Derek Lowe (In The Pipeline).
https://www.science.org/content/blog-post/sarepta-s-approval... ("Sarepta's Approval Woes" (2013))
https://www.science.org/content/blog-post/sarepta-s-duchenne... ("Sarepta's Duchenne Therapy Is A Lot Further Away" (2014))
https://www.science.org/content/blog-post/sarepta-s-day-fda ("Sarepta's Day at the FDA " (2016))
https://www.science.org/content/blog-post/sarepta-gets-appro... ("Sarepta Gets An Approval - Unfortunately" (2016))
https://www.science.org/content/blog-post/gene-therapy-duche... ("Gene Therapy for Duchenne" (2018))
https://www.science.org/content/blog-post/opening-lid-sarept... ("Opening the Lid on Sarepta's Drug Approvals" (2020))
https://www.science.org/content/blog-post/sarepta-tries-agai... ("Sarepta Tries Again" (2023))
https://www.science.org/content/blog-post/sarepta-why ("Sarepta. Why?" (2024))
"The other problem is with viral vector based gene therapy is you can’t have it again. You develop antibodies which prevent it from working again, and it could cause a dangerous immune response."
Just wondering - would it make sense to immune-suppress the patient for a short period of administering of the viral-based therapy.
And as they describe that most gene therapies affect only extra-nuclear DNA, and thus have no permanent effect, wouldn't mRNA work better then in such cases - naturally the tech wasn't there 10+ years ago, yet today thanks to COVID it is here.
That happens to anything recombinant we produce: crops, cattle, bacteria. That even applies to dog breeds.
"Advantageous" changes as the environment changes. Being a large long lived strong dinosaur is advantageous until meteorite? Then being a small mammal is advantageous. A population explosion of locusts ravages all plants successfully, until a fungus infects and kills almost all, thankfully for locusts some of them which were not "the best" survived that one infection.
And the same homogeneity means that developing a defense for any future hostile organism is much more straightforward, just like e.g. developing software that works on windows is much easier than developing software that works on windows, Linux and mac.
Think again about your statement, what you're saying is the fitest is the easiest to manipulate? Thats just mindboggling bad, cause you'd also be a honey pot for all the other bacteria and viruses out there.
(because, it definitely look like gambling, like "investors are behind us right now, so we have the money to do it, so let's do it before money runs out")
I took a look at some of the aftermath reports (i.e. https://pmc.ncbi.nlm.nih.gov/articles/PMC10638066/ and some others) which get into specific details about the course of treatment in several patients who died from this complication. The through-line is an aggressive use of several immune suppressing and modulating therapies to calm the cascade.
I have to admit I can't find any specific discussion about dialysis in that context, so I can only assume that removal of the viral particles would be a case of closing the barn door after the horse escaped.
Maybe a better phrasing of your question would be:
> Why is hemodialysis ineffective for this?
https://news.ycombinator.com/item?id=44609583
https://medcitynews.com/2025/07/sarepta-gene-therapy-fatalit...
Reasons to use AAV: they're going for sustained production of the therapeutic gene, and AAVs are better at doing that than LNPs. LNPs were used in the mRNA COVID vaccine, because they're great at transient production.
To get stable production from an LNP you'd likely have to integrate into the genome, which risks cancer from disrupting oncogenes. You'd also need to package the therapeutic gene with a mechanism of integrating into the genome, like recombinase.
https://www.axios.com/2025/04/18/rfk-jrs-potential-future-ta...
https://kffhealthnews.org/news/article/nih-grants-mrna-vacci...
> National Institutes of Health officials have urged scientists to remove all references to mRNA vaccine technology from their grant applications, two researchers said, in a move that signaled the agency might abandon a promising field of medical research.
I'd be curious what the numbers are for the "good" that this therapy does; is there any way that this therapy is still "worth it" at any scale? but I know little about this area so that's a fairly naive question.
It seems to me to be similar to the approval of the three Alzheimer's drugs which don't really show improvement either- it seems like over the past decade the FDA has wanted to approve drugs that might work for diseases where there was no treatment at all (while saying things "delivering hope"). And it's not gone well, and has not been a good idea.