[HN Gopher] What's going on with gene therapies?
___________________________________________________________________
What's going on with gene therapies?
Author : nehal96
Score : 48 points
Date : 2025-07-15 16:48 UTC (2 days ago)
(HTM) web link (nehalslearnings.substack.com)
(TXT) w3m dump (nehalslearnings.substack.com)
| JohnMakin wrote:
| I have an extremely rare autosomal dominant subtype of a certain
| genetic disorder that affects maybe less than a few thousand
| individuals at any one time in the USA. Much common versions of
| the disorder that affect children have been successfully
| treated/cured with gene therapy. However gene treatment unlikely
| to ever reach people like me because so few are affected by it,
| it's not viable commercially. It's extremely frustrating and I
| struggle with tremendous feelings of anger about it, but I can't
| really do anything short of become a billionaire and fund my own
| treatment. Such is the state of medicine for profit, I guess.
| baggy_trough wrote:
| Wouldn't the same problem occur with any system that has to
| prioritize resources (that is, any realistic system)?
| colechristensen wrote:
| One of the sort of strange things about gene therapy is how
| cheap a custom solution really is. You can arbitrarily
| genetically modify a plant or bacteria for a few hundred
| dollars to the level of arbitrarily picking the letters of a
| gene sequence (or you know, doing some research and doing
| something real) and getting the gene modifying tools
| manufactured very very cheaply.
|
| If you have a slightly different form of a much more common
| ailment, there probably is good hope that eventually patient
| specific gene therapy for you will be something of a routine.
| You may be taking extra risks because of the lack of available
| research, but I'm sure any patient can become well informed
| enough to make the choice for themselves. I'm not saying it's
| commonplace or anything yet, but the tools are there or almost
| there to fix a slightly incorrect single gene issue (like a
| single point deletion or letter swap, etc).
|
| Like just look
|
| https://www.idtdna.com/pages/products/crispr-genome-editing/...
|
| obviously this is for research and not _in vivo_ human
| treatment which takes quite a bit more care and specifics to
| target whatever tissues / organs / whatever is broken in
| you...
|
| but the reagents for doing custom sequence edits are priced for
| research in the hundreds of dollars. sure once an established
| research program finished and got approved they'd spend tens or
| hundreds of millions and charge each patient millions
|
| but it's not insane to imagine a biohacker curing you in their
| garage for $5,000 while only maybe killing you
|
| Given that, I think there's a lot of hope that custom gene
| therapy will become commonplace and relatively affordable.
| rubidium wrote:
| You've taken a very small slice of the total workflow to
| develop cas9 crispr edits. Yes some components are "not crazy
| expensive", but that's not therapeutic production levels. And
| no sequencing. And no bioinformatics. And then zero tissue
| targeting/ delivery or safety studies.
|
| So $5k is a massive stretch. I do think costs are coming
| down. But don't want to oversell current state of "garage
| hacking" either.
| colechristensen wrote:
| Sequencing all of the interesting parts of the human genome
| is $300-$400 and a few weeks wait.
|
| The bioinformatics to find a simple mutation and design a
| crispr fix or one of the other gene therapy methods is
| about 1 grad student week.
|
| I am talking about garage hacking and there sure are a
| bunch of risks and chances of ineffective treatments, but
| researchers used to take a lot more risks and I can see
| folks with degenerative, terminal, or otherwise very severe
| conditions being happy to say fuck it let's try something.
|
| And with an appetite for risk and a fuck it attitude, you
| can try something for less than the cost of a used toyota.
|
| And as mainstream treatments develop, custom gene editing
| as a fully safe therapy option is going to become common.
| mandevil wrote:
| We are not close to that. Gene therapies are still very much
| hit or miss in RCT's, if some biohacker offers you something
| for 5k you are definitely getting scammed.
|
| The first gene therapy approved for in vivo treatment by the
| FDA, Luxterna, was approved in 2017. It treated RPE65
| associated Retinitis Pigmentosa (at an original list price of
| 425,000/eye). Just a few months ago, J&J's LUMEOS trial
| revealed that basically the same process but targeting a
| different gene (RPGR) failed to meet its primary endpoints in
| the Phase III clinical trial (only 22 of 55 patients treated
| showed improvement on at least two measures, and there was no
| statistically significant improvement on the main measure at
| all). At this point, we can't even reliably take a process
| that fixed one gene and apply it to another gene to treat the
| same disease, that's how far away we are from "some dude in a
| garage." Will we get there? Maybe, but the human body is far
| more complicated than software, and analogies based on how
| software work mislead more than they help.
| colechristensen wrote:
| If you were a grad student with RP, you could replicate the
| LUMEOS study drug for $400 + your time for a garage level
| safety self treatment. I can certainly see someone being
| willing to take that risk themselves for a 40% chance of
| improvement to reverse or prevent their own blindness.
| There are many guardrails for safety which are quite
| expensive but the actual materials are absolutely not
| expensive at all.
| mandevil wrote:
| The experience of patients who received Luxterna was that
| the single most important difference in how large the
| improvement was and how many complications they had was
| the quality of the surgeon who delivered the actual
| therapy. The best surgeons saw much better results and
| far fewer complications, and these surgeons are way
| beyond the capability of some grad student in a lab. The
| best surgeons were way better than other licensed,
| trained surgeons! That these sorts of non-gene factors
| dominate the outcomes- and costs- of gene therapy is the
| point that the original article is making.
|
| The articles example for this is Casgevy, a gene therapy
| that can mostly cure Sickle Cell. The problem is in order
| for that gene therapy to work it takes surgeons, full
| transplant teams, super-chillers, chemotherapy, and full
| hospitals to deliver it and for the patient to recover in
| while being carefully monitored. This is what drives the
| cost, and so it doesn't matter how cheap the actual gene
| sequencing or editing is, the rest of the costs dominate.
| This is Amdahl's law, but for costs- the costs are
| dominated by the non-gene editing part of the process and
| so that determines the improvement in cost you will see.
| southernplaces7 wrote:
| But in all seriousness, who would you direct your anger at in
| this case? For one thing, being angry in a general sense
| implies that a fortuitous blend of circumstances is owed to you
| by the world in a broad sense so that your specific, completely
| accidental (of nature) misfortune can be remedied. Secondly,
| many people suffer from much more common conditions that also
| have no remedy so far (i'm an example of such), and this
| doesn't mean that it's the fault of any system or person in
| particular. It's more the case that there are so many
| multitudes of types of suffering that could be made better in
| our world, and only limited, incremental resources for going
| after any number of them over time. Given that, it's obvious
| that many causes of suffering, including illnesses, will be
| left wanting at any given time without it necessarily being
| something that you could fairly fault human agency for..
|
| I mean, do you really believe that in some realistic
| alternative system of organizing society, your specific,
| extremely rare condition would have already been addressed, or
| have had more of a chance of being addressed than under what
| exists now in the world?
|
| Sorry for elaborating so much in this comment, but the
| complaint you make is one i've frequently seen and for the
| reasons above it has never seemed entirely logical to me.
| itake wrote:
| I think they are angry because a solution is available but
| not accessible.
|
| People are gatekeeping resources that would enable access to
| treatment because for big companies, spending $1 to earn $1
| isn't a sustainable business model.
| southernplaces7 wrote:
| My understanding of the comment wasn't that. It was that a
| solution for his adult version hasn't yet been developed
| because it's not commercially viable to do so due to its
| rarity. This of course brings me right back to the points I
| made in my own comment above. Resources are scarce, and
| commercial viability, or at least resource viability for
| all the effort of development, is a factor under any system
| you choose to look at. There are just so many priorities
| out there and we all know this. We can't compare the world
| of our ideal vision of how it should be with what's the
| case. We need to compare what's the case with what's
| realistic, and with was previously the case, and how it has
| changed, either for better or worse.
|
| If on the other hand, a solution for his problem does exist
| and is simply not available, I don't see how that makes
| sense. Why wouldn't it be sold if it were available?
| itake wrote:
| I think we are saying the same thing. Companies chase
| high risk high reward over low risk low reward.
|
| Presumably, curing a genetic disorder for a very small
| number of people using existing technology is low risk
| and low reward.
|
| > Why wouldn't it be sold if it were available?
|
| Just because something works in a small lab doesn't mean
| it's ready to sell. To launch a product, companies need
| to do a lot more: testing, certifications, licenses,
| marketing, training, and more. Sometimes, even when a
| product is finished, companies decide not to launch it if
| their budget or priorities shift elsewhere.
|
| A related example could be unreleased movies like Batgirl
| Or Coyote vs. Acme. The films were completed, but they
| felt their marketing dollars would be better spent on
| other projects.
| toast0 wrote:
| > Presumably, curing a genetic disorder for a very small
| number of people using existing technology is low risk
| and low reward.
|
| I don't know if that presumption is reasonable. Yes, low
| reward; but I suspect the risk/cost for a gene therapy is
| about the same, regardless of the number of people
| affected. You still need to do all the pre-human trials,
| which are still expensive; then you've got to do human
| trials, which are still expensive ... and if there aren't
| enough potential patients, you might not even be able to
| run a reasonable trial. (although the article describes a
| situation of a single patient treatment, you obviously
| can't run a human trial of that). IMHO, that makes it
| higher risk than targeting something that affects many
| more people.
| anon84873628 wrote:
| Perhaps in the future we will have regulation that
| allows, let's call it, "experimental" genetic therapy for
| diseases with a very small patient population, similar to
| what is already allowed for certain terminally ill
| patients. That could reduce the economic barriers to
| treating these groups.
| mandevil wrote:
| > Presumably, curing a genetic disorder for a very small
| number of people using existing technology is low risk
| and low reward.
|
| At the present state of medical understanding, in vivo
| gene therapy is not low risk, just from a financial
| perspective, leaving aside the medical risks.
|
| In 2017 the FDA approved Luxterna, the first in vivo gene
| therapy treatment (it had an original list price of
| 425,000/eye). It fixed RPE65 associated Retinitis
| Pigmentosa. This spring J&J announced that their LUMEOS
| trial had missed its primary endpoint, even though it was
| basically treating the exact same disease, in the same
| way, just a different gene (RPGR). But only 22 of the 55
| treated patients showed improvements on at least two of
| their measures, and there was no statistically
| significant improvement on their primary measure. So this
| stuff is still very much a financial risk, because we
| simply don't understand human bodies well enough to
| predict outcomes in a RCT for gene therapy. And if you
| have to do a Phase III trial to know whether it works or
| not, then you are going to be forced to spend a whole lot
| of money to bring any gene therapy to the market.
| JohnMakin wrote:
| I thought it was pretty clear that's why, but I guess
| people will read what they will. Not sure why you're being
| downvoted - it's extremely angering to have a condition
| that severely limits your quality of life have a cure that
| society easily has within reach that will likely never
| become available to you because market forces deemed so.
| Wouldn't that anger anyone? Like am I supposed to go, "oh
| gee shucks, that's just the all knowing invisible hand, oh
| well?"
|
| Weird comment thread. Not bad, just surprises me.
| anon84873628 wrote:
| I find this comment to be downright insulting to the parent.
| You manage to:
|
| 1) Call them entitled for feeling angry 2) Remind them that
| other people have it worse 3) Imply they're stupid for
| imaging things could work any other way
|
| And then try to defend your obviously immature, unproductive,
| and unsolicited criticism in the "I'm just being logical!"
| excuse.
|
| The parent didn't go on a screed and rage at the world. They
| didn't try to claim their anger is righteous. And they
| certainly didn't ask you to play two bit therapist.
|
| Rather, they shared a totally reasonable and relatable
| emotional response to the situation they are in. I personally
| found it relevant and insightful to the discussion.
|
| I highly encourage you to reevaluate to how you respond to
| these sorts of comments in the future.
| JohnMakin wrote:
| It is, which is why I'm not really going to engage with it
| directly. honestly, this attitude is so insanely common and
| I struggle to understand it personally so I dont really
| engage with it much. In real life people often struggle to
| understand, like, if you look at me I "look" fine, yet, I
| am mobility limited and have to use a cane a lot. They'll
| be casually dismissive about it like "oh, there's gene
| therapies now, someday they will cure you." Like, no, and I
| still have to live with it until and if that day comes (it
| probably will not). Saying things like that diminishes the
| very real struggles I deal with for pretty much no reason
| at all and is really callous, even though people are often
| unaware of how it sounds.
|
| I'm also being purposely vague here to protect my privacy
| but I think most people if they had a condition that (and
| this is all true):
|
| - causes severe pain and limits mobility to the use of a
| wheelchair over a period of time. No ability to exercise or
| have sex after it has progressed enough;
|
| - Limits your ability to procreate because of the above
| bullet point but also because of the high risk of passing
| it off to offspring
|
| - A cure exists but society hasn't deemed you special
| enough to put time into it
|
| That.. wouldn't make you angry a little bit? I don't have
| to even blame anyone or anything to be allowed that. It's
| enormously frustrating. I'm not being entitled by being
| frustrated and angered by it, that idea is of course
| perfectly absurd. As is the idea that the anger needs to be
| "directed" anywhere. I guess I maybe drink a little too
| much and that's where it goes? honestly, who cares? And if
| I may borrow the parlance of the GP comment, their doesn't
| seem very "logical" from my POV. As is the downvoting
| swarms that usually accompany any kind of sentiment against
| the Almighty Altar of Capitalism. I'm not even making a
| critique of it, or offering an alternative, because I don't
| have one, but I don't need to provide one. It does suck,
| albeit for a small amount of people. But I guarantee you if
| you added up the sum of rare but probably treatable/curable
| diseases that we havent spent time on because of the
| rarity, the sum of those people is probably a significant
| chunk of the population.
| JohnMakin wrote:
| Besides how insulting this comment is, which I'm going to
| ignore, I'd just point out a common theme in this thread is
| "limited resources" yet those limited resources are currently
| being incinerated on things like AI sex bots. Seems like a
| bit of a fallacy or cope to me. Research for some of these
| things costs essentially a rounding error. The limited
| resource you're mentioning here is "profit," not actual
| resources. it's not like society can't decide to invest in
| these things instead of the enrichment of a very small group
| of people.
| LinuxAmbulance wrote:
| The fact that for profit medicine is holding up some of the most
| advanced medical treatments in history is really disturbing. As a
| society, there will be a significant benefit, especially once
| it's cost optimized. But we'll never get there if beancounters
| hold it up, preferring short term profits above all else.
|
| I'd love to know if anyone knows what a solution to this problem
| might look like.
| colechristensen wrote:
| Solution: public funding of research which appropriately gives
| intellectual property ownership to the people preventing
| patents and driven by reasonable boards giving away grants to
| researchers and practitioners to find and practice new
| therapies
|
| We're kind of going in the right direction forcing open access
| of publicly funded research, but there's a lot more to do. And
| a big step backward with the insanity of the current
| administration which we can only hope will end soon enough.
| RamblingCTO wrote:
| I think now is a good time to see that privatizing essential
| services was a pretty dumb idea.
|
| The only thing that could work is either have a natural public
| monopoly on the health sector (for essentials) with direct
| democratic control measures (otherwise the "beancounters" will
| corrupt it) or just pour public money on it and hope it sticks.
| It's pretty obvious by now that the market won't regulate
| itself and will not care if people die. If it's not profitable
| enough they won't care (and by they I mean the abstraction of
| individuals who would care but are on distance by
| capital/stakeholders or psychopaths).
| condiment wrote:
| To summarize, the problem with gene therapy is simply that it's
| extremely expensive and the list of qualified clients is
| extremely small. That's because these therapies have been
| necessarily targeted towards ultra-rare and assuredly fatal
| diseases.
|
| That approach developed the technologies, but what if a mass
| market approach is what is required to create the economies of
| scale we need to actually benefit from this science long-term?
| Consider a cure for the common cold. All of the technology
| exists. We can take a tissue or fluid sample and extract viral
| genomes, comparing against a database of over 100k viruses. We
| can develop MRNA vaccines that target specific viral proteins. We
| can do both of these things using current technology in a
| timeframe of less than a day.
|
| To me this is the next great leap. Gene therapy is less a
| technology problem than it is an infrastructure problem, and rare
| diseases cannot support the infrastructure. But there are plenty
| of wealthy people who would pay $10k, maybe even $50k, out of
| pocket to cancel a cold. Rare diseases bootstrapped the tech,
| common diseases can scale it, and once scaled, everyone benefits.
| VirusNewbie wrote:
| Well, rare disease certainly gets people to pilot the tech. I'm
| certainly not going to try some ultra-experimental gene therapy
| to be immune to the common cold or fix my allergies, I don't
| know what the side effects might be.
|
| But if I was staring down some awful rare disease, then sure,
| let's roll the dice.
| searine wrote:
| The issue isn't a technical one with gene-therapy. The issue is
| ethical.
|
| Editing your DNA can be dangerous or even deadly if it doesn't
| work. Modern methods have mostly solved this, but there is
| still a lot of hesitancy due to prior failures/tragic deaths.
|
| It is also ethically foggy. Somatic edits, edits that will die
| with you and do not change your sperm or eggs, are one thing,
| but when you start making germline changes, that impacts
| everyone who may inherit your genes. You may consent to a
| germline change, but will your children? Or your children's
| children's children? You may have the money now to make they
| change, but will they have the money to change it back?
|
| Small genetic changes also have a complex spectrum of phenotype
| outcomes. If you start making germline changes that are not
| found in nature or are under-studied, that can have compounding
| unintended consequences. For example, if you spec into a dozen
| intelligence SNPs, that may also increase your risk for a
| pandora's box of mental illnesses.
|
| So no, economies of scale will not solve this. It would be a
| disaster.
| condiment wrote:
| You're conflating gene therapies vs. the human genome with
| gene therapies vs. viral genomes. In some cases, the
| illnesses are genetic, but this article is specifically about
| how gene therapy companies keep going out of business trying
| to cure rare genetic illnesses! Even if the technology is the
| same, the uses are very different and regulatory approval is
| still required for the application of the technology.
|
| That's not to say there aren't additional ethical challenges
| that would arise if gene therapies were cheap, but the ethics
| concerns you're raising seem like future concerns, relevant
| to a world that does not yet exist.
| mandevil wrote:
| This is actually a lot harder than you think because we still
| don't understand gene therapy well enough to be able to be sure
| that any given treatment works without the really expensive
| part, the Randomized Control Trial. In 2017 a gene therapy was
| approved in the US for RPE65-associated Retinitis Pigmentosa,
| Luxterna, the first in-vivo gene therapy approved by the FDA
| (yay! List price was a mere 425,000/eye). Just a few months ago
| J&J announced that their gene therapy targeting a different
| gene, RPGR, missed its primary end-point, only 22 out of 55
| treated patients showed improvements on at least two of the
| measures in the LUMEOS trial and there was no statistically
| significant improvement on their primary measure. That result
| happened even though this was mostly just "take the thing that
| already worked for Luxterna, and do a different gene." The
| problem is that the human body is far more complicated than
| computers, and does not scale the same way.
|
| This is why regulators are very wary of "Right to Try" type
| stuff, they want to be sure that medical treatments are
| actually effective before they are available to the broad
| public. These sorts of RCTs are still quite necessary, and they
| are the really expensive thing in drug discovery. (Well, it's
| both that they are expensive to run and also they kill all
| sorts of drugs that don't actually work.)
| michaelbrave wrote:
| I think a lot of our diseases if looked at genetically
| instead of symptoms-wise that we will probably find out that
| it's actually multiple conditions that we just group together
| for manifesting in similar ways. I've felt this in my own
| life with ADHD things where it seems to me that there are at
| least 3-4 different types of ADHD and that they respond to
| treatments/medications differently, and this makes me think
| that many other conditions might be similar, especially if we
| start looking at them genetically.
| mandevil wrote:
| This is such a deep hole of complexity. (My wife is a
| pharmacist, I make computers do what I tell them to, and
| she has convinced me that her field is far more complex
| than us software people can imagine.)
|
| To pick one story my wife has told me, take the example of
| Multiple Sclerosis. In the 1970's and 1980's, thanks to the
| MRI machine, there was finally a good diagnosis tool for
| MS: can you see the lesions in the scan? If you can
| congrats, you have MS. If you can't, it might be early MS
| where the lesions are small enough that we can't see them
| (generally they are visible several years after initial
| symptoms). But there were a lot of people who had MS-like
| symptoms and no lesions, so diagnosis of Chronic Fatigue
| Syndrome (named just in 1970, in contrast to MS which was
| identified in the 19th Century) started to rise. Most of
| those people would have been diagnosed with MS in 1950, but
| now we can rule that out and so they go into the new bucket
| instead. What is going on with patients in that CFS bucket?
| It's a mystery. Is it one thing or many? Who knows! Is it
| genetic or environmental? Who knows!
|
| And how does one get original flavor MS? It's not fully
| genetic- comparing identical and fraternal twins we can see
| that it's not purely genetic but there must be a genetic
| influence. The current most accepted theory, according to
| my wife, is basically Long COVID- but for the Epstein-Barr
| virus (what causes Mononucleosis) instead of COVID-19. So
| if your immune system is somehow susceptible to this (the
| genetic component, which we apparently do not understand),
| and it encounters EBV (and there is a bit of bad luck? Who
| knows!) then somehow the immune system gets confused and
| starts attacking your own nervous system.
|
| We computer people are simply attacking much more tractable
| problems.
| bashmelek wrote:
| I have been curious if it would be possible to create a
| business around pet-genetics as a means to improve the
| underlying technology without having to be overly concerned
| about the human factor...granted there will still be ethical
| restraints of a sort
| michaelbrave wrote:
| More likely the profit would then be in dealing with animal
| husbandry types of modifications instead. Cows/chickens that
| don't get sick, that kind of thing.
| pedro_caetano wrote:
| From what I understand the situation is quite the opposite, there
| is a huge pipeline of investment both in startups as well as very
| large corps on the development and application of gene therapy.
|
| As anecdata, Luxturna costs north of a quarter of a million per
| vial, it treats a fairly rare disease (Leber congenital
| amaurosis). Roche still poured millions into development.
|
| Bio-tech, specially in a Medical field, is a very difficult
| business. The strategy for must startups is to get bought by a
| very large pharma company. The issue is that these companies
| often run out of runway, specially when dealing with later pre-
| clinical, clinical, and regulatory costs.
| Fomite wrote:
| It's also just _hard_. Biology is hard. Being a startup in a
| heavily regulated field, rather than the "What if $Industry
| but with no regulations?" of the Uber/AirBnB model, and where
| iteration doesn't necessarily show returns makes life for
| biotech startups difficult.
| NooneAtAll3 wrote:
| isn't that exactly what article is saying?
|
| > Bluebird Bio, once a leader with three FDA-approved gene
| therapies, sold itself to private equity for around $30 million
| earlier this year, a 99.7% decline from their all-time-high
| $10b valuation
|
| *investment* is there, market isn't
| l0new0lf-G wrote:
| Could it be just that gene therapies should be publicly funded?
|
| Taxpayer money has paid for a substantial percentage of research
| around the world, and it doesn't seem necessary that we rely on
| profit-driven private companies for the actual therapies when
| they could be done at publicly funded hospitals too.
| Fomite wrote:
| We really don't have a great pipeline for publicly funded
| developments going all the way to the treatment stage.
| folli wrote:
| This argument is not limited to gene therapies, but would apply
| to pretty much every pharmaceutical product.
|
| One issue is however that the actual costs are not so much in
| early R&D (what the publicly funded universities and hospitals
| are doing), but in the later stage (clinical trials) which
| needs deep pockets and appetite for risk, which only big pharma
| has, because they see a potential big payout.
| steeleyespan wrote:
| I have Alpha 1 Antitrypsin Deficiency which often leads to lung
| and liver transplants (if available) late stage, blood product
| early stage.
|
| It's pretty rare, but there is gene therapy in the works
| promising 2027 timeline or so for availability.
| steeleyespan wrote:
| I was wrong looks like 2030!
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