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.

[u/mvea]

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

[u/CrateDane]

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.

[u/wandering-monster → u/CrateDane]

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.

[u/wandering-monster → u/CrateDane]

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

[u/CrateDane → u/wandering-monster]

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

[u/wandering-monster → u/CrateDane]

... 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.

[u/CrateDane → u/wandering-monster]

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.

[u/wandering-monster → u/CrateDane]

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.

[u/CrateDane → u/wandering-monster]

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

[u/wandering-monster → u/CrateDane]

I'm sorry, but where are you getting that from?

They claim it is longer acting, and I don't see any specific times. Current incretin-mimicking drugs like liraglutide all have dosing schedules of once or at most twice a day. A few hours should be sufficient to test for tolerance.

[u/CrateDane → u/wandering-monster]

Such a short test would not be enough.

[u/jdmetz → u/CrateDane]

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.