What's going on with gene therapies?
nehalslearnings.substack.com
nehalslearnings.substack.com
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.
Then there’s the cost. My single treatment cost $3 million as part of a clinical trial, and lasted about 3 years. Normally, it costs about $1 million a year for my normal factor product, which I had to go back on. So I guess it was a wash and it was nice to be free of the medication for a few years. But it’s definitely not perfect and has its own limitations.
Isn't this a bit contradictory? I mean, if they insert copies of working genes into the cell, it is in nuclear DNA, so when the cells divide, the daughter cells carry the new gene?
I can imagine other cases, for example, progenitor cells were not infected, cells that do not divide, etc...
Thanks for any answer
There are techniques that work on modifying nuclear DNA but from my understanding it's much harder (like using CRISPR) and has a lot more risks for things like causing cancer due to off-site editing.
The scales that this technology works is mind-boggling. 10^12 to 10^14 per kg of body weight of individual viral particles that all must do the same thing, and work correctly at scale. Even a few errors could cause serious problems.
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.
> 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
It’s pretty rare, but there is gene therapy in the works promising 2027 timeline or so for availability.
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.
But if I was staring down some awful rare disease, then sure, let's roll the dice.
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.
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.
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.)
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.
Which is why it was so puzzling to see the response during the last pandemic. More so with people concerned about mRNA vaccines and conflating that with 'DNA changes'. If one is concerned about their DNA, they should avoid viruses and do whatever they can to help their immune system fight them as quickly as possible.
The odds of a virus giving us something beneficial like a placenta are minimal, the drawbacks are just enormous.
There's also the question of, who writes the rules. Often it's industry experts that are already working on the process, and have incentives like keeping others out or licensing their own IP.
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.
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.
Let's just cut out the middle man.
It is so bad that for a lot of treatments, getting them to people costs upwards of hundreds of millions of dollars. And almost all of these efforts fail.
This would mean the government would need to breed (and pay for) lab animals, small and large (from mice to primates). Would need to pay more for medical care, would need to collect (and pay) people to try out experimental drugs and treatments on. If these treatments or drugs have adverse effects, the government would need to shoulder sometimes lifelong payments and care to these people. It would need to cover all this knowing that in 90% or so of cases the whole effort was for nothing.
This is, to put it mildly, not happening.
I'd love to know if anyone knows what a solution to this problem might look like.
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.
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).
Once you have centralized the ability to edit genes, most of that machinery can be repurposed for less 'profitable' endeavors.
A very crude comparison would be time sharing a radiotelescope. If you want to build one to run school experiments, it's prohibitive. But once you have one, you can use any spare capacity to allow for observations that would be impossible to justify economically.
But chimpanzees can’t, regardless of how much effort they put in.
So a time-sharing system 1 million times more complex cannot be created by people who are probably not even 1000x smarter than an average chimp.
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.
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.
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.
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.
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.
Also one of the benefits of cheap to produce unique gene therapies is once you figure out one treatment, similar treatments for slightly different genetic anomalies affecting the same tissues will become much easier to apply. In other words once you have a delivery mechanism down targeting something specific, the gene payload can be swapped at much lower incremental cost.
We are not yet at the point where we can effectively just substitute genes and everything works in vivo, and until we get to that point every fix requires its own Phase III trial, and that (both the costs and the chance of complete failure) is what drives the R&D expense through the roof, even if a single infusion could fix the problem, unlike the other examples I cited.
1: Existing gene editing platforms don't work well for large genes: there is an effective base pair limit for all existing techniques in vivo. Most Stargardt's genes, to pick another similar to Luxterna as an example, are above that limit, and will require new techniques not yet approved in vivo.
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.
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.
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?
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.
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.
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.
Weird comment thread. Not bad, just surprises me.
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.
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.
For the first one, my arguments above, for the second one, fair enough, it happens to anyone suffering enough from something, and though I've tried to calm and redirect it when I feel that way, it's hard to pull off.
You also didn't explain, and i'm honestly curious: is this something that has no remedy for someone who's an adult, or something that has a treatment, but it's too expensive for you?
>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.
Well yes, but there are also many much more widely devastating problems that we can also treat, but which haven't been fixed yet, and the reasons for that are way too complex to blame any one thing, or capitalism. Governments and all their immense resources are around too, yet they also don't quite seem to get around to fixing so many things that have solutions. Again, comparing the real world with your desires is never going to work. The world needs to be compared with its previous states for a fair sense of perspective.
Being sick doesn't make a person free of possibly feeling entitled or coming to unreasonable conclusions, nor does it make it wrong to question their feelings. I did so fairly politely. In my comment above, I was honestly asking for them to clarify who they think is worth being angry at, and why. I also explained reasonable reasons for why it's misdirected to claim as unfair a very general thing that's removed from you specifically only because it hasn't yet gotten around to creating relief for a problem you have, in a complex world full of problems that can't all be solved all at once or in just the way any one person desires.
This is a reality that all of us live with, so how the hell is it insulting if someone points it out?
>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
No, but they commented about their problem in a comment thread where people comment back and debate randomly. I don't give shit one about being anyone's therapist, but if you mention something personal, in a comment thread of all things, expect the possibility of someone responding with questions or opinion, like you yourself are doing. Should I feel insulted too?
I too have a long-term, very tedious and problematic health condition I need to deal with day by day, and it has no real medical remedy yet. I try to temper my frustration though. I understand that some things just aren't easy to fix.
You refer several times to argument and debate but you're tilting at windmills. The OP didn't make an argument. The closest thing is "Such is the state of medicine for profit, I guess." which is more of a resigned, bitter observation than overt indictment of capitalism.
If you want to use that as a prompt to say why no other funding model is better, then ok fine. But there are polite ways to do it which acknowledge the legitimacy of the person's feelings.
What's different about my comments is that they address things actually in the text and are in the spirit of bystander intervention and setting the tone of the commons.
I’ll pose an argument to the rationalist crowd that I feel likes to think and feed deeply off these types of discussions:
say I’m destined to create the cure for cancer or bring about the singularity or whatever. I’m not, but let’s say I was. And I fall and hit my head one day and die because some billionaire decided that my condition wasn’t worth investing a miniscule fractional percentage of his wealth.
would that be wasteful?