I would suggest you contact MiniCircle and ask them. Please post if you find out.
See this page: Follistatin injections via Minicircle plasmids? They're recruiting new volunteers for trials in Honduras
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Hello, I’ve gotten a reply from the CEO and Founder of MiniCircle. He said the cost is 25K and the duration of the effects is 2 years.
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I’m confused about the “duration of effects is 2 years” comment.
If what they are doing is truly gene therapy, and the are getting integration into the genome / transfection of the gene, it doesn’t seem like there should be a “duration” limitation. That is sort of the key benefit of gene therapy; its a permanent fix (or so I thought).
Does anyone here have more information on what exactly they are doing, and why it would only be effective for two years? I know they say they are using plasmids in the process.
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I must admit I agree that the statement of having effects for two years sounded odd. I am not enthused by some of these gene therapies as they seem to potentially cause more problems than they solve.
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I’ve asked the Bing AI which uses GPT 4 two questions regarding this. Don’t take this as absolute fact because I’ve known it to make a lot of errors but I think it gives a pretty good answer on the mechanism of why this is the case. This is why I think AAV vectors might be the go to and as you mentioned the patent expires 2023/2024 and offers a more permanent solution.
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I think it’s near useless because it still makes stuff up. Don’t trust anything it says unless it links to a study that says exactly what it said.
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Hmm, Seems fairly cheap compared to many others (In the millions)
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Interesting information coming out of GPT4, thanks for posting. I wouldn’t trust it on any single detail, but the general information is probably reasonably accurate.
Perhaps its a reasonable start for longevity gene therapies…if they are only temporary fixes.
Permanent changes this early in the world of gene therapy, unless used in serious, fatal diseases, seems like it may be ill-advised. The AAV vector is a non-targeted vector I believe, so the risk of off-target effects (being inserted into the middle of an otherwise fully functional gene) can mess with things, and may be impossible to correct.
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The poster from Bryan Johnson in your post above does say it is reversible, zoomed in on that section:
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MIT tech review has an article on the Minicircle attempt. Setting aside the issues of whether this effects aging per se, what evidence is there that plasmids are even an efective approach in humans?
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I agree errors could lead to unforseen consequences. I saw a video with David Sinclair and although I largley believe he is a grifter for resveratrol and NMN he was talking about a type of gene therapy that can be induced or reversed using antibiotics. The hypotheitcal situation he used was a person got into a car accident and they take antibiotic to active dormant healing genes. He also mention taking the antibiotic to silence them again. With things like crisperoff and new varaints of gene editing technique I think it will be safer to edit the genome permantly if there is a kill switch. But as you said its early in gene editing so who knows how long till these methods are practical.
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Here’s an extended video, documentary style, with firsthand accounts of people undergoing Minicircle’s therapy in Honduras.
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Good point. yes - I’ve done work in a gene therapy startup. The area of inducible / conditional expression of specific genes that you insert into an organism is a well-proven and frequently used approach in animal model development. You can insert genes into mice, for example, that get “turned on” when exposed to tetracycline. This allows you to turn on, and turn off that gene in question whenever you want. I suppose you could take that approach in humans, but the entire medical system is going to have to move along with this as there is the risk of someone accidentally turning on specific genes in someone who has had this type of gene therapy (when, in a hospital, for example, someone gives a patient tetracycline for other purposes).
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Just finished watching it.
Apparently the Phase 1 Trials have concluded in August 2023. Does anyone have access to the results? I couldn’t find them on the website.
I can also try contacting them. 
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Note to self:
Don’t take ketamine in an isolation tank.
That even seems kind of dangerous ex ante.
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I’d like to hear more about AAV going off-patent. Do we have any intel on how much of the very expensive gene therapy prices are due to that? As things are going, I think I will pay 25k to get the FST in Feb, both to test that I personally have no adverse reaction, and to buy me a year of effects while AAV hopefully goes off patent and comes down in price.
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so the risk of off-target effects (being inserted into the middle of an otherwise fully functional gene) can mess with things,
Im no expert on how this works, but on my call with Dr Sewell of Ingetrated Health, he said some of the DNA does make it into the nuclues (which is important for the therapy to work), but it doesn not get included into our chromosomes. I asked GPT to elaborate:
“In most cases, AAVs do not integrate their genetic material into the host’s genome. Instead, the AAV DNA exists as independent, circular episomes (extrachromosomal DNA) in the nucleus. This reduces the risk of disrupting the host’s genes, which can lead to cancer or other unintended consequences.”
I followed up, asking:
Can AAV gene therapy occasionally get incorporated into our chromosomes and disrupt an existing gene?
ChatGPT: Yes, AAV gene therapy can occasionally result in the integration of the therapeutic DNA into the host’s chromosomes, though this is relatively rare compared to other viral vectors. Here’s how and why this might happen:
Integration Mechanism:
- Random Integration: While AAVs are primarily episomal and do not actively integrate into the genome, random integration events can occur at a low frequency. This happens when the AAV DNA inadvertently becomes inserted into the host’s genomic DNA due to cellular DNA repair mechanisms or other processes.
- Site-Specific Integration: AAVs can also integrate at specific sites. For example, integration into the AAVS1 site on chromosome 19 is well-documented. This site is considered a ‘safe harbor’ as it’s less likely to disrupt essential genes or regulatory elements.
Disruption of Existing Genes:
- Insertional Mutagenesis: If AAV DNA integrates randomly into the genome, it can potentially disrupt existing genes or regulatory elements. This disruption can lead to a loss of function of the affected gene or unintended consequences like the activation of oncogenes or inactivation of tumor suppressor genes.
- Consequences: The consequences of such disruptions depend on the function of the affected gene and its role in cellular processes. In some cases, it could lead to cellular dysfunction, disease, or cancer.
Factors Affecting Integration:
- Cell Type: Some cell types may be more prone to integration events than others. For example, dividing cells might present more opportunities for integration due to the dynamic nature of their DNA.
- Vector Design: The design and serotype of the AAV vector can influence its integration profile. Researchers are continually working to design vectors that minimize the risk of harmful integration.
Summary:
While AAV gene therapy has a lower propensity for integration compared to other viral vectors, it can occasionally integrate into the host’s chromosomes and potentially disrupt existing genes. This rare event is a consideration in the risk-benefit analysis of AAV therapies, and ongoing research and monitoring are aimed at understanding and mitigating this risk. As with any medical treatment, the potential for adverse effects is weighed against the therapeutic benefits, particularly for serious or life-threatening conditions where few other treatment options exist.
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Gene therapies are coming, but I’m not sure who will be able to afford them any time soon:
New gene therapy, to be priced at $4.25 million, has already transformed children’s lives
A new gene therapy for an ultra-rare disease will have a wholesale cost of $4.25 million, making it the world’s most expensive drug.
The one-time treatment, Lenmeldy, won US regulatory approval on Monday to correct the underlying cause of a hereditary condition called early-onset metachromatic leukodystrophy, or MLD.
MLD is a fatal disease in which infants sometimes start to lose the ability to walk and talk. Orchard Therapeutics said the drug’s price “reflects its clinical, economic and societal value” in a statement Wednesday.
Full story: World’s Most Expensive Drug Is Now $4.25 Million Gene Therapy (Bloomberg)
Another gene therapy:
A question for people who follow this space more closely:
When do you think these two things are likely to happen for a broader range of gene therapies?
- RCTs for consenting/willing adults
- On-demand treatments available more broadly at a more reasonable cost (say under $10-50K)
I was wondering about these interesting candidates:
- APOE2 for everyone and especially APOE4 people
- SIRT6 over-expression
- “Short sleep” genes
- VEGF-A?
I’m assuming this not going to happen in the US first, but in perhaps in places like Vitalia in Roatan/Honduras first.
What do you think?
I will throw out a guestimate, but nobody really knows. I would say:
- 5 to 10 years for RCTs for consenting/willing adults (for age-related therapies) - you could argue that MiniCircle is alreadying doing this in Roatan.
- 10 to 20 years, but perhaps more likely 30 years for the reasonable cost aspect (but again, MiniCircle is doing their preliminary non-permanent “gene therapy” for $30,000 or so, so we’ll see.
There are some gene therapies available today: Gene therapies currently available
The issue is that there are so many uncertainties.
About 20 years ago the gene therapy startup scene was hot in the SF Bay Area, companies like Avgenics and many others were getting tons of funding and everyone though the future was bright and happening quickly.
I had friends in the gene therapy business here in the SF Bay Area 20 years ago when a FDA-approved gene therapy trial that was taking place went horribly wrong. A young 19 year old man who was participating in the trial died when his body responded very negatively to the viral vector they were using. His death hit all the major newspapers in the USA at the time, front page. It killed the entire industry virtually immediately. All the funding went away, and all the startups died in pretty short order. And the venture money would not look at the field for a long time… like 15 years went by before they would start investing again.
We have some gene therapy biologists here in our forums so perhaps they can comment.
But I think that most of these gene therapy companies today are still using viral vectors (the shell of a virus that can integrate into our DNA) to get the gene segments integrated, but there are still many problems with this as these are random integrations. Since you don’t know where the newly inserted gene is going, it could disrupt an existing well-functioning gene. I don’t know how well the work is going for targeted gene therapies, so that you can specifically insert the new gene segment into a targeted spot of the genome. perhaps someone else here has current knowledge in this area.
You also have random political factors that can hugely impact the work of biotech startups; when George Bush was elected president he shut down all the embryonic stem cell research in the country virtually overnight. Could a similar situation happen with gene therapy if it seemed to be politically convenient? Its certainly possible.
While a lot of good progress is being made in gene therapy now, it seems to me there are still significant hurdles to overcome to make it more broadly available and less expensive. I believe some of the hurdles are things like doing targeted delivery of the genes (vs. random), optimal delivery techniques to maximize transfection rates/ integration in the right areas of the body to be effective, and navigating the intellectual property landscape to get access to the different technologies a given company may need to use to delivery the therapy.
MiniCircle is the first non-standard type of gene delivery company to be tried, in terms of it being outside the purview of the FDA, etc. Minicircle: This biohacking company is using a crypto city to test controversial gene therapies (MIT Tech Rev)
You just have to hope that nothing bad happens with any of the Minicircle patients; as that could again kill the industry very quickly.