tl;dr:
- Minicircle is claiming implausible, nigh-impossible numbers in plasmid capabilities and delivery efficiency: several orders of magnitude above the state of the art.
- Even if they really have cracked #1, follistatin is very unlikely to result in 30% lifespan extension. Or muscle growth, at least with the follistatin levels they’re claiming. Placebo effects are real, however.
- Twitter link here: https://twitter.com/yashgaroth/status/1782497300876591431
Expression levels and half-lives 3
The impracticality of minicircles 9
There are no controls and their numbers are (very probably) fake 12
The FDA sucks, but this isn’t why 13
Introduction
For those unaware, Minicircle (https://minicircle.io/ & https://minicircle.clinic/) is a company offering a non-viral plasmid gene therapy for follistatin. According to multiple reports, they are charging ~$25,000 USD for treatment. I will be sourcing some information from their woefully inadequate published documents, including a 1-pager and a preprint.
There are many reasons to be suspicious of their claims. Here’s the main one: If plasmids could do even a fraction of what Minicircle is claiming, the entire half-trillion-dollar biopharma industry would be replaced overnight.
Minicircle aren’t doing some magic to overcome the severe limitations of non-viral gene therapy. In fact they’re doing the opposite, while claiming they’re getting plasmids to work at least 1,000x better than the state of the art. Biologists have been trying to make plasmids useful as a gene therapy vector for decades – even a modest 25% increase in expression levels will get you a paper, maybe a patent.
You might read that and think “Wow, Minicircle must be an incredible company, I should invest and/or pay them a new car’s worth of money for an injection”. I get it! Biotech has been promising breakthroughs for decades, and has mostly failed to deliver. But there isn’t some grand conspiracy to keep medicine shitty. It’s just a hard problem to solve.
Minicircle’s results are either wrong, or simply fake. I’d be overjoyed if they’re hitting the numbers they claim. It would be the equivalent of cold fusion for biology, made by two random sketchy dudes. We could stop spending hundreds of billions of dollars a year coaxing antibodies out of Chinese hamster ovary cells, and just grow plasmid in a bathtub instead.
Even if they somehow weren’t fabricating their numbers, you wouldn’t see the purported effects from follistatin at the levels they claim; certainly not the 30% life extension. The results so far, if you can call them that, seem to be placebo effect.
I was content to let the whole thing run its course, but I’ve met a few people now – a couple of whom I respect in other matters – that seem to take everything published by Minicircle (and one suspicious academic lab) at face value. But when this all comes crashing down, it will reflect poorly on the DIYbio field and make the FDA look better by comparison. I can’t abide either of those.
A truly exhaustive expose would be far longer, but I hope to provide some of the due diligence that has been sorely lacking. Extraordinary claims require extraordinary evidence, and the evidence provided so far is ~zero.
Plasmid gene therapy sucks
For reference, a plasmid is just a circular loop of DNA. Plasmids are incredibly simple to design and manufacture, and they can be injected over and over again. But that’s about it.
Compare that reusability and cost advantage with viruses like AAV, which are eye-wateringly expensive to manufacture and can usually only be injected once due to the immune response, even if the patient is on the mandatory massive prep dose of immunosuppressants.
Yet there’s a reason every actual gene therapy uses viruses: viruses have evolved over millions of years to deliver DNA into a cell’s nucleus very efficiently. They get injected, bump into a cell, enter it, and ferry the DNA straight to the nucleus.
A plasmid, by comparison, must be forced inside the cell. There are two main ways to do this: 1) electrocute nearby cells to open holes in their membranes (“electroporation”), or 2) use a positively-charged substance to counteract the electrostatic repulsion between the negatively-charged cell membrane and the negatively-charged DNA. This can be either a polycationic polymer or a liposome. In any case, the efficiency of this step is unfathomably low, though it is better with electroporation.
After that, the few plasmids that made it into a cell still need to get inside the nucleus. Their only option is to wait for the cell to divide, and sneak in when the nucleus dissolves during mitosis. This isn’t a guarantee, and in fact is woefully inefficient. I’m talking fractions of a percent here, even in the best-case scenario.
Unless you’re pounding cheeseburgers, your fat cells (which Minicircle claims to target) are not dividing that often. Fat cells don’t produce a lot of protein either, making them a horrible target for gene therapy even conditioning on the (very unlikely) success of the previous steps.
Tweaks like “minicircles” (different from Minicircle the company, though the company seems to be named after them) don’t meaningfully change the equation. The only novel thing Minicircle seems to claim is “reversibility” of the gene therapy, which is irrelevant to how much protein it can produce (and, indeed, counterproductive). There’s a reason we don’t try to make plasmids reversible, but more on that later.
The fact that Minicircle are claiming the numbers they are after a tiny, fifty microgram injection of polyethyleneimine (PEI)-coated plasmid makes it absurd on the face, which should be obvious to any competent biologist. Why? Well, read on.
Expression levels and half-lives
Follistatin, like most small proteins, is cleared from the bloodstream fairly rapidly - its half-life is about 90 minutes. E.g. if you just inject some follistatin protein, half of it will be destroyed after 90 minutes. An antibody, thanks to FcRn recycling and sheer mass, has a half-life of about a month.
For a protein being actively produced in the body (as in gene therapy), once the production of a protein reaches a steady state with its degradation you reach the circulating level: as much is being produced as destroyed.
Minicircle claims that serum follistatin levels are boosted by ~20 nanograms per milliliter (ng/mL) of blood after a single injection. Calculating from a blood volume of 5 liters, that means 100 micrograms of follistatin pumping through your veins at any given time.
If the plasmid were instead producing an equal amount of antibody, the half-life would be increased over 300x. Here’s a visual comparison of the area under the curve (AUC), which functionally translates to protein efficacy:
Read up on protein pharmacokinetics if this seems interesting (it shouldn’t, but I don’t judge). Anyway, follistatin in red, and an antibody in blue. Note that there’s even more AUC for the antibody off to the right of the graph…but it gives you some idea.
That would mean a constant circulating antibody level of 30 milligrams (100 micrograms * 300) achievable after a single injection. Not quite enough to replace all monoclonal antibody therapies in one shot, but you could just do another plasmid injection. Or ten more. Or a hundred.
We can argue about the flex in the numbers: AUC calculation, the equivalency of gene expression between constructs, different plasmid size. But even if it’s off by a couple orders of magnitude, just inject more plasmid. There’s no functional limit with plasmids like there is with viruses. Minicircle’s treatment costs maybe ten cents per dose, but more on that later.
On top of that, Minicircle are claiming to use only fifty micrograms of plasmid, and the shittiest transfection method (PEI) aside from naked DNA, which makes it even more ludicrous. Doses are typically 100x higher in human trials, and using a method like electroporation into muscle which is substantially more effective.
Maybe after reading this, Minicircle will claim to increase the dose (and attach a spark gap generator to the syringe to make it seem more science-y). Or maybe claim that they’ve been doing it all along. The nature of fraud is that it becomes harder to spot after shortcomings are pointed out and plastered over. Just keep that in mind.
Anyway, let’s say instead they upped the dose to 10 milligrams and used a multi-needle electrode into muscle, instead of shitty PEI. That’s, very conservatively, a 1,000x increase in gene expression efficiency per treatment. With their claimed numbers you’d be able to have thirty grams of an antibody in your blood. Hell, you could be on every monoclonal antibody therapy at once. After a single treatment.
If Minicircle were claiming their +20 ng/mL boost after a treatment like that, I’d be less suspicious. But they’re not. They’re doing the equivalent of plasmid homeopathy and still claiming insane results. This is what most obviously suggests their numbers are fabricated.
The point is: if Minicircle’s claimed numbers are even in the ballpark of being correct, this would easily replace nearly the entire biopharma industry, not to mention receiving a handful of Nobel prizes. Most of the drugs on this list could easily be replaced by plasmid gene therapy if it worked. And it’d cost a few dollars, not $50,000-200,000 or more a year.
You might think greedy big pharma wants to build billion-dollar facilities full of specialized equipment and pump expensive reagents into them with a firehose, but I’m sure they can still make a buck selling a plasmid instead. The vast majority of biologists didn’t get into biology to make money – and a good thing, too, because the pay is shit.
The joy of not having to deal with Chinese hamster ovary cells deciding to stick slightly different sugars onto the antibody for no goddamn reason…it’d make any biomanufacturing technician ecstatic.
In fact, when a technology came along that let us skip making biological molecules in vats, we jumped for it - mRNA vaccines make patients into producers of a protein, instead of needing to grow it in bioreactors, vastly simplifying manufacturing. What Minicircle is claiming is a breakthrough more unbelievable, and of greater importance, than a perfected mRNA vaccine. Please feel free to argue in the comments about whether mRNA vaccines were developed by the lizard people to give young athletes heart attacks, but that’s a separate issue.
On follistatin
No one is arguing that sufficient levels of follistatin won’t boost muscle mass. But all the research studies so far either use huge quantities of AAV, with its concomitant downsides, or they’ve genetically engineered an animal to have the gene in every cell in its body. Which, as you can imagine, makes things a lot easier. Doing it with plasmids is…not really on the table.
How much follistatin do you need to make a difference? Rather annoyingly, studies that jam a bunch of follistatin gene into animals via viral vectors often don’t quantify the levels of circulating follistatin (e.g. here or here).
That latter article, though, is interesting: it’s the only primate study we have of a follistatin gene therapy. They (of course) use AAV. Even then, in the version with the weaker (but still very strong) muscle creatine kinase promoter instead of the strong CMV promoter, there was only a marginal increase in muscle mass. To clarify, components like vectors and promoters have a multiplicative effect: AAV will deliver much more DNA into cells than a plasmid would, and CMV would instruct much more protein to be made versus another, weaker promoter.
Also note that that study used the contralateral leg on the same monkeys as a control, meaning there was no systemic effect. Growth was limited to the injected muscle, even with the CMV-powered version. This is likely due to differences in protein circulation between species - mice are a lot smaller than macaques, which themselves only weigh ~6 kg. In a mouse the follistatin is able to circulate through the whole body, delivering a systemic effect. Consider scaling that up to humans with a single point injection.
The only follistatin quantification in the primate paper is nanograms per milligram (ng/mg) of muscle tissue, which is absolutely not a direct proxy for serum ng/mL. But it is reported as 25, a curious coincidence. If I wanted a plausible fake number for my follistatin gene therapy, but I wasn’t very good at biology, I’d pick 25 ng/mL.
There is one paper that quantified follistatin levels after gene therapy (AAV, natch) in mice and found an increase to 15 ng/mL after treatment, along with some buff mice (Figure 1a in the paper). Note, however, that they found normal follistatin levels in mice are undetectably low: “0 ± 0.1 ng/ml”. Meaning 15 ng/mL is, in mice, at least a 150x increase over baseline, and possibly much more. Now, those buff mice might still be rippling with muscle with a less than 150x increase. But it’s an interesting data point.
Side note: what if you could naturally boost follistatin levels to a level far beyond what Minicircle claims to achieve? I’m talking 70 ng/mL or more. Only about 20% of people alive today are able to do this, but for them it’s pretty simple: get pregnant. The researchers note that those levels hold with an earlier study that was specific for the long variant, which showed an even higher level. Pregnancy, like any other physiological process, is complex. Another interesting data point.
N.B. Minicircle say micrograms per mL in their 1-pager, because they’re too stupid to know the difference between micrograms (ug) and nanograms (ng). That might not be a big issue to you, but if someone were injecting me with mysterious drugs, I’d want them to know the difference. Go check it out before they fix and reupload it:
Fully tackling the “follistatin increases lifespan by 32.5%” paper is a topic for another day. I’d ignore it, but it seems to be a big part of Minicircle’s advertising and Bryan Johnson tweets about the same. But, in brief:
The paper was fully funded by Bioviva, which is a…similar company to Minicircle. They’ve been pushing a viral gene therapy for follistatin and telomerase for longer than Minicircle has been around. Aside from the obvious “mistakes” discovered on PubPeer, it is difficult to conclusively prove fraud in academic papers. But anyone can make up numbers: 26.74. See? I just typed that in. Magic!
The PubPeer and the two corrections on the paper are worth reading, but aren’t strictly damning on their own. The image fuckery may well have been an honest mistake, but claims like “well our Chief Scientific Officer isn’t an “employee”” are telling.
I can only say that if something’s too good to be true, it usually is. This appears to be beyond any lifespan extension seen with telomerase in mice (except in those joke papers where they knock out telomerase and then add it back in); especially suspicious when the telomerase is only being delivered to a small fraction of cells in the mouse’s body, long after birth. I won’t even start on the inanity of monthly dosing with a live, replication-competent virus.
It doesn’t cost anything
I got a good laugh when I heard how much Minicircle is charging. There’s no magic in their plasmid design, despite the secrecy. There was no extensive R&D to justify those prices either; it’s all off-the-shelf components and gene sequences.
Let’s design a plasmid:
- You have a promoter/enhancer sequence that tells the cell to produce a lot of the gene. This’ll be the CMV-IE promoter or its variants, though you might want to use a tissue-specific promoter so the protein isn’t exposed on antigen-presenting cells.
- Then the gene itself, follistatin, optionally codon-optimized.
- Then a polyA sequence (SV40 or something) which also tells the cell to make a lot of the protein.
- Optionally, an S/MAR sequence that, when included in an intron, will drive episomal replication of the plasmid. Here’s an example.
- Finally your plasmid backbone. The backbone is composed of an origin of replication, which allows E. coli bacteria to replicate the plasmid, and an antibiotic resistance gene, which forces the E. coli to carry the plasmid to survive. A few options here:
- Leave the backbone in the plasmid, which causes the cell to silence (disable) it eventually
- Chop it out with the minicirclization process, which is a pain in the ass and causes the plasmid to lose supercoiling (making it much worse at getting into cells)
- Use an engineered backbone which is too short to cause silencing, e.g. the nanoplasmid
- If you’re stupid, a “reversibility” cassette which I’ll get into later
There are plenty of other considerations for good plasmid design, but if this is interesting go read Molecular Biology of the Gene.
So you get the plasmid synthesized from scratch for a couple thousand dollars. Genscript is my usual go-to supplier, or you can go with one of the dozens of others. Then you shove the plasmid into an E. coli cell, and grow that cell in bacteria food (“media”) with an antibiotic corresponding to the resistance gene on the plasmid. You find the cells that survive in that situation, meaning they’re carrying the plasmid. You grow more of them on more food. After you have a lot of cells, you crack them open and pull out the plasmid.
It may sound like I’m oversimplifying this, but any competent molecular biologist should be able to design and order a plasmid that meets the specifications of an equivalent vector to whatever Minicircle is using. Probably a better one, and it would take them less than a day. Putting it into a cell, growing more of those cells, and making hundreds of milligrams of plasmid takes maybe a week, most of which is hands-off work. Again, anyone working in a molecular biology lab should be able to do this with their eyes closed. The bacteria eat powdered ~Vegemite and you shake them in a flask overnight. That’s it.
Even turning the resulting goop into injection-grade plasmid isn’t hard. There’s a kit - the Endofree Gigaprep or its equivalents. Bacteria go in, injectable plasmid comes out. Say you went with Thermo’s version of the kit and paid $350 to purify 30 milligrams of plasmid (2 preps per kit). That’s about 11 bucks per milligram. Of course, Thermo overcharges for everything and you can find a perfectly equivalent kit elsewhere for half the price.
Minicircle is claiming 50 micrograms of plasmid per injection, which works out to about 3 cents per dose for the plasmid component. Of course there’s the “transformation polymer” which they’re now admitting is polyethyleneimine (PEI). It also costs nothing at these doses. Anyway, you mix some PEI and plasmid together before injection. I guess the syringes cost twenty thousand dollars.
I’m glossing over a lot of details here because non-biologists don’t want to read about the intricacies of plasmid production, and biologists will just be skimming over this whole section. But this entire process is neither difficult nor expensive.
The impracticality of minicircles
I mentioned the plasmid backbone (origin of replication and antibiotic resistance gene). This is standard in every plasmid if you want bacteria to make the plasmid for you. However, if you just inject the whole plasmid into a mammalian cell, the backbone will eventually cause the cell to “silence” the plasmid, through mechanisms I won’t get into here. In addition, the longer/larger a plasmid is, the worse it is at sneaking into the cell and nucleus, so excising a chunk of it helps there too.
20+ years ago, some researchers thought “Wait, what if you just cut those parts out before you inject it?” and minicircles were born. They did this by using integrases; enzymes which see two specific DNA sequences and kind of criss-cross them. Recombination is the technical term.
You put those two sequences in the plasmid, flanking the backbone part. Functionally, this means you start with one plasmid, add the integrase, and end up with two plasmids: one is your minicircle, and the other is the backbone. Imagine twisting an O into a figure-8, and squeezing the middle bit until the two little ‘o’s pop apart. The integrase is doing the squeezing.
The problem is, this makes purifying the plasmid a huge mess. By purification, I mean going from a disgusting soup of bacteria to something you’d want to inject into your body.
Your first option is doing this recombination inside the E. coli, which has a low efficiency and is a delicate tightrope of conditions. You encode the integrase gene in the cells, and tell the cells to start making it at a certain time. Do it too late, and you end up with a bunch of un-recombined plasmid. Too early and your yield is shit, because the minicircles can’t replicate without the backbone. Low yield also means you get more bacterial junk carried through the purification, making the plasmid unfit for injection. In either case you also end up with a variety of side-products that are difficult to remove.
Alternatively, you can do it after the plasmid has already been purified, by making a bunch of integrase protein and incubating it with the plasmid. Then you end up with plasmid which is no longer supercoiled.
Imagine torsioning a rope along its axis and then splicing it together at the ends, retaining that torsion in the rope circle. If you cut the rope, it unwinds. This twisting happens naturally with plasmids in bacterial cells, and is called supercoiling because we wanted a cool word for it. A supercoiled plasmid is compacted, as you can imagine the torsioned rope circle would be. This aids massively in getting the plasmid inside cells and nuclei.
Also, all commercial plasmid prep kits are specific to supercoiled plasmid: if they stuck to regular unwound DNA, they wouldn’t be able to separate the plasmids from the bacterial genomic fragments.
If there was a legitimate plasmid gene therapy, no doubt its designers would at least investigate using minicircles (small ‘m’ again). But they would need access to an ultracentrifuge and cesium chloride to actually separate the good plasmid from bad, along with a boatload of other equipment and quality control. I strongly doubt Minicircle is doing so.
Anyway, the newer nanoplasmid backbones avoid most of those issues. Minicircle might well have switched to ripping off Aldevron’s patent. It’s only circumstantial, but they seem to be walking back references to actual minicircles anywhere but their company name. Also, it bears repeating: even with all these tweaks and improvements, plasmids are still nowhere near the capabilities Minicircle is describing.
The reversibility is bogus
Now for my favorite part, the “genetic killswitch”. Just take some tetracycline and the plasmid is gone!
When I first heard this, I (and any other molecular biologist) thought Tet response element. There’s only a few ways of implementing it as they describe, and they’re all terrible. That leads me to believe Minicircle isn’t actually doing it (and if they are, they should stop), but let’s play along.
Tet response elements use a protein discovered in tetracycline-resistant bacteria. Bacteria resist antibiotics in a couple ways: they either make an enzyme that breaks down the antibiotic directly, or they push the antibiotic out of themselves faster than it can get in. In either case, they’re making a lot of protein to do that job.
Proteins are expensive and bacteria are lazy, so one of them figured out “What if I make a little bit of protein that detects tetracycline, and it tells me to make the tetracycline-removing protein only when tetracycline is around?”. After all, bacteria aren’t usually sitting in tetracycline.
Scientists eventually discovered this trick and said “Hey here’s a protein that will stick to a certain DNA sequence, but only when tetracycline is present”. Then they used it to turn gene expression on (or off) with some clever engineering. If this sounds interesting, go read Molecular Biology of the Gene as I recommended earlier. And Molecular Biology of the Cell; they’re both great.
So what might Minicircle be doing with this?
- The Tet-Off option. Here, you integrate a modified Tet response protein and its DNA recognition sequence in the follistatin promoter. If there’s no tetracycline, the cell makes the protein, but with tetracycline present, it blocks expression of follistatin. This means you can temporarily lower gene expression while you’re on tetracycline, but if you stop taking it the expression jumps right up again.
Seems worthless, and it is. Plus the basal expression level is much lower than you’d get with an always-on system that doesn’t mess with Tet. And you’re loading up the plasmid with the Tet gene, which adds bulk (lowering efficiency) and producing a foreign protein that your body can attack.
- The Tet-On option. The (relatively) more plausible approach is using a self-reinforcing Tet-On circuit, akin to flipping a permanent switch after a sufficient single dose of tetracycline. This substantially reduces protein expression while in the active state, and requires complicated engineering that has never been tested in humans. You also need to add multiple regulatory proteins to make the switch work. And, of course, it balloons the size of the plasmid which tanks your efficiency even more.
The crazier option would be that the Tet-On activates a plasmid-destroying enzyme, e.g. a nuclease, targeting a sequence in the plasmid to chop it up. I won’t get into the possible negative effects that can have if it gets loose in your genome. Craziest would be inducing cell death – no cell, no plasmid.
In any case, you’re still making foreign proteins in these cells - the Tet response protein is bacterial, after all. Eventually you might get an immune response to said foreign protein that leads your immune system to kill off any cells with the plasmid. Then, no more plasmids for you, unless you use one that isn’t doing some retarded reversibility hack.
It also adds an absurd amount of complexity - entire separate gene circuits to control Tet expression are crammed into the plasmid, bloating it and tanking its ability to get inside the cell. Simpler is better. In fact there’s almost an exponential negative correlation between plasmid length and uptake efficiency. You really don’t want to include anything extraneous unless it pays for itself in boosting gene expression.
The baffling part is that reversibility is unnecessary. The best thing I can say about Minicircle’s treatment is that it’s harmless: you’re not going to overdose on follistatin (especially with their method). The irony is that if you just use a regular non-minicirclized plasmid, expression fades after a few months anyway and you can go get another dose.
Side note: I enjoyed watching this interview of one of Minicircle’s MDs. I call your attention to this timestamp (12:05) where he claims that because the plasmid is “from E. coli”, the antibiotic destroys it. If they were injecting live E. coli bacteria, then sure. But they are not, and…please don’t inject yourself with live bacteria. He goes on to say a lot of other stupid stuff in that interview – very charitably, he’s dumbing it down for the audience.
There are no controls and their numbers are (very probably) fake
Let’s say you had $25,000 burning a hole in your pocket. Someone offers to grind up that money and inject it into your arm. They claim all kinds of insane effects from this injection. Hell, some rube guy on twitter is calling it “Captain America tech”! You don’t understand biology but hey, there was a peer-reviewed paper and even some bad graphs. People don’t just make up numbers or fake research, right?
Would you, perhaps, have more energy and motivation after that injection? Start working out more, with all that energy and motivation? Do you think it’s possible that that motivated exercise would cause you to gain a whole 2 pounds (whoa!) of fat-free mass over 3 months, as Minicircle claims in their 1-pager?
Scenario 1: you got the placebo and it was all in your head. Whoops! Just kidding, Minicircle isn’t running any placebo-controlled studies (I wonder why).
Scenario 2: you got the “real” injection and the placebo effect caused all sorts of psychological benefits. Yes, you can have placebo effects even if you get the treatment.
This kind of thing seems increasingly common. “Oh man I paid way too much for this protein/peptide/stem cell/supplement and I feel so much better. One weird trick the FDA doesn’t want you to know!”
Just do push ups. I hear steroids are pretty good now, and the feds seem to have given up on regulating them, if you really want to biohack it.
On to faking numbers. The quantification of circulating follistatin in their “studies” is being performed by one guy at Minicircle, as they admit in their preprint. Follistatin isn’t a common medical blood test, because it doesn’t diagnose anything. But it’s not hard to quantify with an ELISA, a kit for which is commercially available.
What I would recommend for anyone considering putting money into Minicircle (as a patient or investor) is to find an existing recipient and get a blood sample. I’d recommend a regular venous draw (not fingerstick). Of course, more samples are better, along with some regular peoples’ blood as a control.
Any qualified molecular biologist with a minimal lab setup will be able to quantify follistatin levels in blood. At least the ELISA won’t be run by someone at Minicircle.
The rest of the numbers reported in the preprint (LDL, CRP etc) are sourced from third-party diagnostic labs. They do spend six pages inflating all those numbers into graphs, but the data shows no significant change for any of them. Maybe LDL, but even that’s dubious.
The FDA sucks, but this isn’t why
I doubt Minicircle is actually pursuing FDA approval for their follistatin treatment, despite their claims. I hope they do submit an application, though, because even the FDA deserves to laugh. All I’ve found so far for their “trial” is this. Note that participants have to pay for their own testing, and there are no controls.
I hate the FDA as much as the next guy, but they exist for a reason. Nowadays that reason seems to be approving drugs that don’t work and cost six figures per patient per year. Originally, though, they were formed because hucksters would peddle snake oil to gullible rubes people.
If you want to demolish the FDA, you need to have a credible alternative. Safety testing is the minimum baseline, though as I’ve said, Minicircle’s treatment is likely harmless. Then again, so is injecting saline.
Proving efficacy is the next step, and equally important. But before (incredibly) expensive human trials, you should at least have the decency to come up with a biologically plausible story for how you’re overcoming piss-poor plasmid delivery and expression rates, to express a compound that has, at best, a mixed relationship to any outcomes you might care about.
Anyway, thanks for reading.
-Max Berry maxberry@gmail.com
P.S. I would like to express my gratitude to those who reviewed, commented and offered suggestions on the draft. I won’t name you here, even by initials, in case this all blows up in my face. But you know who you are.