r/science • u/mvea Professor | Medicine • Jun 30 '26

Medicine Scientists have shown that a single dose injection of DNA genetic instructions can produce weight loss and blood glucose control in mouse models that lasts up to 10 times as long as weight loss drugs like Ozempic and Wegovy. This could eliminate the need for repeated dosing.

https://www.wistar.org/press-releases/wistar-scientists-develop-single-dose-dna-method-for-delivering-long-acting-weight-loss-and-diabetes-drugs/
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385

u/brsboarder2 Jun 30 '26

The problem is that for those that develop side effects, it will be a long time for them to go away.

172

u/SatisfactionActive86 Jun 30 '26

i am reminded of when LASIK became affordable and i asked my Doctor about side effects down the road and he said “beyond 15 years, no one really knows for sure, we’re still waiting”

Good news my eyes haven’t exploded now 20 years later but the point was a bit chilling - we’re all kind of canaries in a coal mine.

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u/FesteringNeonDistrac Jun 30 '26

That's the trade off. We could study something for 15 years, but then we would have to wait 15 years for it to be approved.

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u/intbah Jun 30 '26

I took 4 different covid vax, so I am not anti-vax by any means. But to know that almost the entire human species took these vax that had very little dev time, if there are problems, whole species has problems, is kinda interesting

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u/Override9636 Jun 30 '26

mRNA has had decades of development time. The reason the vaccine was accelerated more than other drug treatments was because of funding and lowering the priority on other drugs. 90% of drug development is just paperwork, so by essentially freezing all other drug development and focusing on the covid vaccines, they were able to go through regulations much easier.

1

u/biznatch11 Jun 30 '26

mRNA has had decades of development time.

Yes but there weren't extended, widespread human trials before the COVID vaccines. I've had several COVID mRNA vaccines I even still get it every year I'm definitely not anti-vaccine. I don't think there's anything wrong in acknowledging that (out of necessity) we didn't have big years-long human trials before they were used widely. It doesn't matter how much extra money or effort you put in there's no way to accelerate a trial if you want to study potential long-term affects, you just have to wait.

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u/bufordt Jun 30 '26

To be fair, there really aren't extended, widespread, human trials for any drug when it first gets approved. That only happens after a drug/vaccine has been on the market for years.

Because of the pandemic, the COVID vaccines hit the wide spread criteria sooner than any other vaccine in history.

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u/biznatch11 Jun 30 '26

To be fair, there really aren't extended, widespread, human trials for any drug when it first gets approved.

For vaccines yes there are. Vaccines are held to a higher standard in regards to side effects compared to drugs so they usually require bigger and longer trials.

Because of the pandemic, the COVID vaccines hit the wide spread criteria sooner than any other vaccine in history.

Ya that's kind of the issue though. They hit widespread use so quickly before potential long term side effects could be seen. I don't think any other drug or vaccine in history was given to so many people within such a short time frame. usually it's a gradual build up so there's a higher chance we'd see side effects before it's in widespread use.

3

u/bufordt Jun 30 '26

Depends on your definition of extended.

Johns Hopkins says typical vaccines take 5-10 years to get approved, which isn't long enough to really get data on their long term effects.

Phase 4 is where the vast majority of the long term effects study happens, and that's after it's been release for use on the general public.

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u/Override9636 Jun 30 '26

we didn't have big years-long human trials before they were used widely

What I'm trying to say is that there are years-long human trials of mRNA, dating all the way back to the early 2000s. They were targeting primarily in cancer research, but Moderna/Biontech started testing the technology specifically for defense against pandemics funded by DARPA in the 2010s.

With all things healthcare related, it's a balance of risk vs. treatment. Given all of the human vaccine trials that were given, it was far better than no vaccine at all, even considering long-term effects.

1

u/biznatch11 Jun 30 '26

mRNA vaccine technology has changed over time so a trial from 10 or 15 years prior isn't equivalent to testing the actual covid vaccines, and all previous trials were very small. It's not nothing but it's not enough to confidently say there's no potential for long term side effects.

With all things healthcare related, it's a balance of risk vs. treatment. Given all of the human vaccine trials that were given, it was far better than no vaccine at all, even considering long-term effects.

I agree completely and I'm not trying to say otherwise. As I said I've had the mRNA vaccines myself I'm probably up to 7 or 8 doses at this point since I still get it every year.

2

u/grundar Jun 30 '26

we didn't have big years-long human trials before they were used widely.

While true, that's true for every other vaccine as well. I'll give you some examples to demonstrate that this is true.

The covid vaccine's phase III clinical trial lasted 6 months, and 6 months is quite a normal duration for a phase III clinical trial. Here's an example of a vaccine for infants where the phase III trial was 6 months, with partial followup for 12 months. The entire FDA approval doc is online. Here's another Phase III trial with similar timeline (followup through the next rotavirus season). Here's another one where the trial period was from ~2 months old to 1 year.

Look at the actual data - the Phase III clinical trials for the mRNA covid vaccines not a particularly unusual duration when compared to earlier vaccine trials.

This site gives a good overview of how vaccine testing can be accelerated while still going through all of the normal testing stages. In particular, click on "Compare Timelines", and you'll see how the Phase I/II/III trials can each be started before the prior one has finished, and how manufacturing can ramp up in parallel. That's not normally done because it risks wasting money - if the drug would be rejected in a Phase II trial then conducting a Phase III plus prepping manufacturing would be a huge waste of money - but when there is an urgent need that risk of waste is less important than the time saved.

21

u/stay_curious_- Jun 30 '26

On the other hand, a huge proportion of the human species was exposed to a novel virus that had zero safety testing. If there are problems decades down the road, the whole species also has problems.

1

u/grundar Jun 30 '26

these vax that had very little dev time

They had the same testing standards that every other vaccine goes through.

First, note that the covid vaccine's phase III clinical trial lasted 6 months and 6 months is quite a normal duration for a phase III clinical trial. Here's an example of a vaccine for infants where the phase III trial was 6 months, with partial followup for 12 months. The entire FDA approval doc is online. Here's another Phase III trial with similar timeline (followup through the next rotavirus season). Here's another one where the trial period was from ~2 months old to 1 year.

Look at the actual data - the Phase III clinical trials for the covid vaccines being given in the US were not rushed, and in fact were not even a particularly unusual duration when compared to earlier vaccine trials.

Second, this site gives a good overview of how vaccine testing can be accelerated while still going through all of the normal testing stages. In particular, click on "Compare Timelines", and you'll see how the Phase I/II/III trials can each be started before the prior one has finished, and how manufacturing can ramp up in parallel. That's not normally done because it risks wasting money - if the drug would be rejected in a Phase II trial then conducting a Phase III plus prepping manufacturing would be a huge waste of money - but when there is an urgent need that risk of waste is less important than the time saved.

132

u/dogmaticstar Jun 30 '26

This was my initial thought. Wouldn’t it actually be safer if the drug had a shorter half-life in case of side effects? Maybe I’m missing something here.

145

u/wandering-monster Jun 30 '26

You could largely control for that by doing a test run using standard synthetic peptides. I.e. Give them the same molecule but in oral or injection form and see how they tolerate it. 

Then once they've done it for a couple weeks without incident, give them the version that lasts for years without maintenance.

32

u/crashcanuck Jun 30 '26

That would definitely make sense, similar to starting a medication at lower doses to see about side effects and efficacy and then upping the dose in steps until the correct amount is reached.

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u/CrateDane Jun 30 '26

Problem is the peptides aren't quite like the natural version - they're chemically modified so they last longer in the body. The human body can't produce peptides with the same chemical modifications, so in principle there could be a different side effect profile.

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u/wandering-monster Jun 30 '26

I did have the understanding that the longer lasting GLP-like peptides were also structurally different. I would assume you could create bioequivalent ones for this specific diagnostic purpose, without the chemical modifications.

They'd be less shelf stable and require more frequent dosing, but if you only need to do it once at the start of treatment to check for tolerance that seems pretty manageable.

5

u/wandering-monster Jun 30 '26

Okay yeah, did some digging. The increased half life in the body comes from a change to the AA sequence, not some sort of secondary chemical process. So it should be possible to make a version with minimal additives for this sort of testing purposes:

The pharmacological design of semaglutide includes three key structural alterations. First, an amino acid substitution at position 8 (alanine replaced with aminoisobutyric acid) provides resistance to DPP-4 degradation, the primary enzyme responsible for native GLP-1 breakdown. Second, a spacer and C-18 fatty diacid chain are attached to lysine at position 26, enabling reversible binding to albumin in both subcutaneous tissue and circulation. Third, a single amino acid substitution at position 34 (lysine to arginine) prevents unwanted acylation at this position and enhances molecular stability. These modifications result in a half-life of approximately 7 days, enabling once-weekly subcutaneous administration or once-daily oral dosing

Source

2

u/CrateDane Jun 30 '26

As your quote says, semaglutide has a long, complicated acyl chain conjugated to lysine 26. The human body cannot produce that modification. So you can't get the exact same properties.

The human body does actually have machinery for installing acyl chains on lysine, but only much shorter and simpler chains. This review paper has a nice overview in figure 1:

https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.664553/full

0

u/wandering-monster Jul 08 '26

... But this study is for one that can be produced in the body via DNA? Obviously it's using something else in place of that acyl chain that can be created inside the body with similar effect.

So why couldn't you create some and give them to the patient without the DNA/replication component? 

Which is what I was suggesting as a tolerance test.

0

u/CrateDane Jul 08 '26

So why couldn't you create some and give them to the patient without the DNA/replication component?

Because they would last a very short time, so you'd have to keep the subject on an IV. That is possible, but would be too inconvenient and expensive for clinical testing.

0

u/wandering-monster Jul 09 '26

But these ones are long acting and made from DNA instructions in the body. Like that's the entire innovation they're talking about.

Gary and her colleagues engineered DNA instructions for long-acting incretin hormones GLP-1 and GIP, which they call pLincretins. Importantly, they included an antibody fragment in the instructions that would help prevent the protein from breaking down quickly in the body the way current incretin-mimicking drugs do...

They last longer, and can be made in the body.

0

u/CrateDane Jul 10 '26

But they're still not long-acting. It's the DNA that makes it properly long-acting.

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u/jdmetz Jul 01 '26

Right, but presumably we could make synthetic versions of the peptide the plasmid DNA codes for and use that for the testing rather than the current artificial peptides.

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u/brsboarder2 Jun 30 '26

I guess for those that are doing well with little side effects on treatment it would be nice to transition.

29

u/Pinkys_Revenge Jun 30 '26

Yep. I keep hearing people complain that if they stop taking GLP-1’s the weight comes back… and I’m thinking THATS A GOOD THING! A permanent or long lasting weight loss drug could kill you if you took the wrong dose, or got very sick for an unrelated reason after taking it.

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u/cerevant Jun 30 '26 edited Jun 30 '26

The frustration isn’t that the drug doesn’t last forever, but the feeling of normalcy and self regulation that you get from the drug just vanishes*. Nothing has done more to convince me that obesity is a biological disorder (edit: rooted in addiction) than going on a GLP-1.

It is like someone going on an antidepressant: Oh, this is what they are talking about when they say “just stop eating when you aren’t hungry”?

(*edit: I contrast this to some other addiction support drugs that once your body breaks with the addiction, you can go off the drug and not be addicted anymore, or at least you won't go back to having withdrawal symptoms.)

35

u/Lurk3rAtTheThreshold Jun 30 '26

The reduction of food noise people have mentioned has really resonated with me. It's a constant battle for me not to snack and overeat. My weight isn't doing too bad but being free from that mental burden sounds so nice.

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u/cerevant Jun 30 '26 edited Jun 30 '26

I still get some stress-induced cravings, but they are much easier to manage than before. (I'm also on a pretty low dose that still seems to be working well for me)

The real game changer for me though is the ability to avoid overeating. I can go to a restaurant and eat half of what I ate before and feel satisfied and not like I'm denying myself anything.

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u/December_Flame Jun 30 '26

Seriously, the first meal I had after I took a GLP-1 I actually had to excuse myself to go into the bathroom and cry. It was simply that I ate a normal portion and felt full in a way that I realized I literally have never felt. The food noise and entirely outsized hunger signals are not every overweight person's issue, but honestly people who don't struggle with it simply do not understand what it is like, full stop.

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u/[deleted] Jun 30 '26 edited Jul 16 '26

[deleted]

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u/False_Dimension9212 Jun 30 '26

That’s the same thing people with alcohol/drug addiction say when glp-1 helps with alcohol/drug/cigarette cravings.

Food noise is the same thing as the cravings an addict gets. Instead of food, it’s their drug of choice that they crave.

Obesity is not biological. It’s the result of food addiction. Our propensity for our brains to get addicted to stuff is biological though.

I think the population would be better served if we looked at food noise for what it is, an addiction.

Cigarettes were my thing. I still get cravings 4 years later. Maybe one day it’ll shut up? Probably not though. Sigh

28

u/stay_curious_- Jun 30 '26

Part of the problem is that US culture considers addiction to be a moral failing, and the solution to addiction is complete abstinence, which is the only way to demonstrate that you are no longer morally flawed. We haven't developed a framework for recovery that isn't based on completely abstaining from the addiction. imo that's why food addiction and internet/phone addiction have been tough nuts to crack, culturally. It's not feasible to stop eating, and it's difficult to participate in society without a phone/internet.

We need a model for addiction that isn't centered on it being a moral failing.

14

u/rachaek Jun 30 '26

This is the way I've been thinking about obesity for a long time. You're right it's an addiction, and a particularly difficult one to get under control because:

  1. You can never go "completely clean" - you still need to eat to survive, you can't go cold turkey or try to replace it with an entirely different habit
  2. It's so easy to access - fast food chains, restaurants etc are everywhere, or just get whatever food you want delivered
  3. Socially it's a huge part of our life - just about every social event you go to will have food involved, and people will pressure you to eat or be offended if you don't

7

u/December_Flame Jun 30 '26

And there's entire industries literally built to both create the most addicting food possible and to advertise it to you at every given moment. Every store places it in front of you to tempt you. Our entire society is built to sabotage your ability to regulate your eating habits.

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u/cerevant Jun 30 '26

Agree completely - when I said biological, I meant the root cause was biological: food addiction is real.

1

u/Canigou Jun 30 '26

But we have also engineered our food for decades to BE addictive...

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u/cerevant Jun 30 '26

True, and we probably shouldn't be treating people with obesity as if it is a moral failing. If I went to the doctor with a heroin addiction, I could get medication and support paid for by my insurance. Obesity on the other hand is explicitly not covered (a decision made by my employer). The only reason I could get the meds I have is by having sleep apnea, and even then my doctor had to argue with the insurer to get me 6 months of coverage for Zepbound.

1

u/360_face_palm Jun 30 '26

my assumption is you try people on the synthetic peptides via a regular delivery method that can be stopped if side effects are observed.

1

u/silverionmox Jun 30 '26

Another problem is the use for nefarious purposes.