What's going on with gene therapies?

https://nehalslearnings.substack.com/p/whats-going-on-with-gene-therapies

by nehal96 • 1 year ago

73 61 1 year ago

nehalslearnings.substack.com

JohnMakin5• 1 year ago

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_trough2• 1 year ago

Wouldn't the same problem occur with any system that has to prioritize resources (that is, any realistic system)?

outworlder2• 1 year ago

Maybe not. Because such as system, by design, would have to create a lot of common, shared infrastructure.

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.

colechristensen5• 1 year ago

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• 1 year ago

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.

mandevil6• 1 year ago

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.

southernplaces74• 1 year ago

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.

itake2• 1 year ago

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.

anon848736283• 1 year ago

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.

JohnMakin5• 1 year ago

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• 1 year ago

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.

colechristensen5• 1 year ago

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• 1 year ago

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).

reliabilityguy• 1 year ago

Even with 100% public healthcare system you have budget constraints. What’s better to provide one treatment for a rare gene decease or cure 10 cancer patients?

condiment2• 1 year ago

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• 1 year ago

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• 1 year ago

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.

condiment2• 1 year ago

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.

mandevil6• 1 year ago

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.)

michaelbrave2• 1 year ago

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.

bashmelek• 1 year ago

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

michaelbrave2• 1 year ago

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.

edge172• 1 year ago

A lot of the technology is regulated by FDA requirements, which apply to humans but not animals. Some of these requirements are challenging engineering problems - like how to do certain type of liquid transfers without exposing the contents of a container to the atmosphere, etc. There are lots of tools for doing liquid transfers that mimic what a human would do, but FDA places a different bar when it comes to developing a controlled manufacturing process.

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.

pedro_caetano• 1 year ago

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.

Fomite2• 1 year ago

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• 1 year ago

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

edge172• 1 year ago

The other thing no one wants to say is the technical software/hardware talent in biotech is not as good as broader tech, and the people in charge of these projects are usually coming from a science background first and a technology background second.

l0new0lf-G• 1 year ago

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.

Fomite2• 1 year ago

We really don't have a great pipeline for publicly funded developments going all the way to the treatment stage.

folli• 1 year ago

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.

thechao• 1 year ago

Right. Because your average citizen has a few hundred thousand dollars for their rare congenital disease. My bet — just wild eyed speculation — is that most of this stuff is paid for by the govt through sone sort of insurance-like subsidy. That means the risk is really borne by the tax payer.

Let's just cut out the middle man.

spwa4• 1 year ago

It's less the research and more getting a treatment to people. Governments around the world refuse to pay for this, and in fact demand that various risks and expenses be paid by pharma companies, with mostly negative results.

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.

steeleyespan2• 1 year ago

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.

steeleyespan2• 1 year ago

I was wrong looks like 2030!

iamleppert2• 1 year ago

I had hemophilia gene therapy. It worked for a period of time but the results were not permanent. The problem with many of the gene therapies is that they do not change the nuclear DNA, they just insert copies of working genes into the cell. If a cell dies, it’s gone. The results aren’t carried through to new cells during division.

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.

JPLeRouzic3• 1 year ago

I am sorry you experience this disease. I have a question: You said "they do not change the nuclear DNA, they just insert copies of working genes into the cell ... The results aren’t carried through to new cells during division."

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

iamleppert2• 1 year ago

The working genes they insert are just into the cell envelope itself, not into the cell nucleus. There are actually a lot of DNA that is free floating around in the cell, and are used during protein synthesis, called episome or non-integrated DNA. This is distinct from the DNA inside the nucleus, which gets copied from generation to generation.

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.

puzzlingcaptcha• 1 year ago

AAV-based vectors are specifically non-integrating. Wild-type AAVs can integrate, but in the absence of rep protein they will instead persist in the cell nucleus in the form of episomal concatemers - long, circular DNA structures containing multiple copies of the virus DNA. These will not replicate when a cell proliferates - they will instead dilute with each division. This makes them desirable for treating diseases affecting post-mitotic tissue like muscle, less so for, say, bone marrow. Unless transient expression (but not as transient as with NLPs) is what you want.

What's going on with gene therapies?

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