[HN Gopher] Third patient dies from acute liver failure caused b...
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Third patient dies from acute liver failure caused by a Sarepta
gene therapy
Author : randycupertino
Score : 140 points
Date : 2025-07-18 18:26 UTC (4 hours ago)
(HTM) web link (www.biocentury.com)
(TXT) w3m dump (www.biocentury.com)
| OsrsNeedsf2P wrote:
| Their stock is down 90% over the last 6 months, 37% today. That's
| not good.
| NooneAtAll3 wrote:
| stock price barely mean anything in recent years
| financetechbro wrote:
| Not for biotech. The stocks in this segment are very
| sensitive to trial outcomes and drug efficacy
| bboygravity wrote:
| Stocks in biotech also very sensitive to coordinated naked
| shorting and cellar boxing by hedge funds.
| simmerup wrote:
| Damn, gene therapy is so promising too
| barbarr wrote:
| 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.
| cyberax wrote:
| Lipid nanoparticles have exactly the same problem. They
| mostly concentrate in the liver.
| bgnn wrote:
| Wouldn't anything concentrate in the liver?
| amelius wrote:
| Could hemodialysis prevent this?
| EA-3167 wrote:
| 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.
| actionfromafar wrote:
| But maybe as treatment if liver problems are detected?
| EA-3167 wrote:
| 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 wrote:
| Yeah I was suspecting they would do the treatment with
| immunosuppressants. Immune response is an unpredictable
| killer.
| amelius wrote:
| 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.
| khazhoux wrote:
| 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?
| amelius wrote:
| The main reason for my question was this:
|
| https://news.ycombinator.com/item?id=44609583
| goda90 wrote:
| Hacker News Guidelines > "Be kind. Don't be snarky.
| Converse curiously; don't cross-examine. Edit out
| swipes."
| wiz21c wrote:
| 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")
| fsckboy wrote:
| 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 wrote:
| 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.
| forgotpwagain wrote:
| A thread from yesterday about why gene therapy hasn't reached its
| potential: https://news.ycombinator.com/item?id=44573193
| trhway wrote:
| Interesting point there:
|
| "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.
| leereeves wrote:
| mRNA vaccines like the Pfizer and Moderna COVID vaccines
| don't enter the nucleus nor have a permanent effect. The mRNA
| breaks down after a few days.
| sampl3username wrote:
| Sarepta's drug uses AAV to deliver the payload. I wonder why they
| chose AAV instead of lipid nanoparticles.
|
| https://medcitynews.com/2025/07/sarepta-gene-therapy-fatalit...
| ceejayoz wrote:
| Probably because the HHS secretary is vehemently opposed to
| lipid nanoparticles.
|
| 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.
| SoftTalker wrote:
| They've been working on this for years. It's not anything to
| do with the current administration.
| downrightmike wrote:
| Yeah, if not for Germany, the covid vax wouldn't have been
| unreachable.
| barbarr wrote:
| 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 wrote:
| I thought lipid nanoparticles were less prone to generate a
| immune reaction.
| snitty wrote:
| 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.
| Flux159 wrote:
| A bloomberg archive.ph article about the same topic -
| https://archive.ph/9qB0t
| DangerousPie wrote:
| https://www.science.org/content/blog-post/sarepta-sarepta
|
| Thoughts from Derek Lowe (In The Pipeline).
| perihelions wrote:
| Also Derek Lowe's previous ones as context (subset I could
| quickly find),
|
| 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))
| snitty wrote:
| 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 wrote:
| 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.
| barbazoo wrote:
| 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 wrote:
| If your body doesn't reject gene therapy, you might live
| longer and reproduce more.
| barbazoo wrote:
| I can see that now, thank you.
| catlikesshrimp wrote:
| 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 wrote:
| 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.
| ygjb wrote:
| Sigh. Covid was a serious illness. We were lucky and able
| to leverage science that had been in development for a
| long time to vaccinate against it. We have a deep
| understanding of many immune mechanisms, and can
| effectively treat people against some diseases. Vaccines
| are super effective (until the virus evolves and then
| they aren't).
|
| This is also happening with other types of pathogens -
| antibiotic resistant illnesses are on the rise because we
| used quickly created defenses to eliminate all but the
| strongest versions of them. We have very few effective
| anti-fungal medications, and most of those are very
| risky.
|
| If we were good at developing defenses for homogeneity,
| farmers all over the world wouldn't be fungi destroying
| the monocultures we depend on for modern agriculture
| (bananas and corn are really great examples). Estimates
| are that as much of 30% of global crops are lost to
| fungal infections; I sincerely doubt that homogeneity is
| the panacea you assume it is.
| mattigames wrote:
| From Google:
|
| > Making fungus-resistant agriculture is challenging
| because fungi share many cellular similarities with
| humans, making it difficult to develop fungicides that
| target fungi without harming plants or humans.
| efitz wrote:
| 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 wrote:
| 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 wrote:
| 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 wrote:
| Ok, so you want the CIA only backdoor?
| klipklop wrote:
| 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 ;-).
| cyanydeez wrote:
| 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.
| gary_0 wrote:
| Apparently the treatment costs $3.2 million.
| https://en.wikipedia.org/wiki/Delandistrogene_moxeparvovec
| scoot wrote:
| That seems very expensive for assisted suicide
| ricardobeat wrote:
| Why does the Wikipedia page treat this as a publicly available
| treatment when it is still undergoing trials?
| ygjb wrote:
| Probably because of this: Delandistrogene moxeparvovec was
| approved for medical use in the United States in June
| 2023.[3][7] It was developed by Sarepta Therapeutics,
| together with Roche, and is manufactured by Catalent.[8]
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(page generated 2025-07-18 23:00 UTC)