Let’s continue our dive into gene therapy with one of my favorite papers. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6876218/
In this study, researchers delivered three longevity-associated genes (FGF21, αKlotho, and sTGFβR2) to mice using a gene therapy cocktail. These genes target metabolism, heart function, and kidney health—three areas that typically decline with age. Here’s why this is a big deal:
Obesity & Diabetes? Reversed. Mice fed a high-fat diet lost weight and saw their diabetes symptoms disappear, just by tweaking how their cells handled energy.
Heart Failure? Improved. The therapy improved heart function by 58%, meaning it could help tackle the leading cause of death worldwide.
Kidney Disease? Protected. Mice treated with this gene therapy avoided the typical kidney damage seen with age-related conditions.
What’s most exciting is that a single gene therapy cocktail—combining just two of the three genes—was able to treat all of these diseases simultaneously. Imagine being able to tackle multiple age-related health issues with just one treatment!
This approach could be a game-changer in how we think about aging and disease. Instead of targeting one condition at a time, we might be able to treat aging itself by addressing the root causes of multiple diseases.
What do you think—are we on the verge of a breakthrough in how we fight age-related diseases?
See this similar paper here targeting TERT and follistatin: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9171804/
Do these papers pass our threshold of believability? Are we concerned that one of these papers had a few post publication amendments? I may circle back to poke holes in them (if I can find any) at a later time. Feel free to beat me to it!
I have yet to give those papers a thorough read, but the follistatin one made me think of another version of gene therapy where the clinicians claim their plasmid vector of transfer allows all changes to be reversed.
https://minicircle.io/wp-content/uploads/2024/04/fstpreprint.pdf
My genomics knowledge is certainly lacking, but what are your thoughts on viral vs. plasmid derived gene therapies?
My suspicion is that a big part of this discussion revolves around integrating vs. non-integrating gene therapies, so let’s start there.
At a high level, viral gene therapies use a viral vector (the capsid or container) to deliver a genetic payload into a cell. That payload can then integrate into the host’s genome if the lysogenic machinery is part of the payload—but that doesn’t necessarily have to be the case.
Plasmid therapies, on the other hand, involve non-chromosomal DNA that stays outside the host’s genome but can still express the proteins it encodes independently. In most cases, plasmids don’t come with the machinery that promotes integration with the host genome, but it’s not an absolute safeguard against integration either. Additionally, a plasmid cargo still needs a vector to gain access into the cell.
In the follistatin gene therapy paper, the authors use a plasmid (the genetic cargo) to encode instructions for follistatin. They deliver this via polyethyleneimine (PEI), a cationic polymer that helps get the plasmid into cells—so PEI acts as the vector here, instead of a virus.
Now, the superiority of either approach really depends on the use case:
Integrating Gene Therapies (more commonly viral-based, since many naturally have integrating machinery that can be included as part of the cargo) are ideal when you want a one-time, permanent fix—for example, in conditions like sickle cell anemia, where a single gene mutation needs to be corrected. In this case, you’d want the therapeutic gene to integrate into the genome for long-term expression and potentially a cure with just one treatment.
Non-integrating Therapies (more commonly plasmid + non-viral vector based) are ‘better’ when you want temporary gene expression. For example, if you're priming the body to fight a new pathogen or delivering a protein with a temporary therapeutic effect, plasmid-based therapies are argued to be more practical. These are also great for delivering proteins that need short-term action but shouldn’t stick around indefinitely, especially if there’s a risk of side effects from prolonged exposure.
That said, I don’t see why viral/non-plasmid strategies couldn’t do these things as well. In fact, many such strategies are in development.
Other Considerations for Viral vs. Plasmid-Based Therapies: Viral Vectors: These also come with higher risks like immune responses, insertional mutagenesis (which can potentially lead to cancers), and limited payload sizes. There are some neat solutions to these in the research sector that we should chat about in the future.
Plasmid Vectors: Generally less immunogenic, but they offer shorter-lived expression, meaning you might need repeated doses to maintain effects. The big benefit in my opinion is they deliver a much larger payload when compared to viruses. Not relevant if you are aiming for a single gene therapeutic but I feel it's the big draw.
Now, About the Follistatin Paper... I’ll hold back some of my critiques of the paper that are beyond the scope of your question, but let me address the safety aspects they mention:
Inherently Transient Expression: This is generally true for plasmids since they don’t integrate into the genome. However, I’m cautious about saying this is 100% guaranteed. There’s always a small risk of integration, even with non-integrating strategies, although the probability is low.
Drug-Inducible Reversibility: The paper mentions this, but it’s not clear how exactly they plan to achieve it. They didn’t include details about the plasmid construct or any antibiotic kill switch, which would be crucial to back up their claim. If such a switch were tied to any potential integrations, in theory, it could allow them to kill off any cells where integration occurred—but more details are needed here. This strategy also isn’t 100% effective, by the way.
Excision of Transfected Tissue: This one made me laugh a bit—“Oops, we made a tumor—CUT IT OUT!” Brilliant and novel, guys. Thanks for mentioning it. While theoretically possible, it doesn’t seem like a reasonable safety net for a clinical approach. Given that cancer development is one of the big concerns with these therapies, and cancer is notoriously slippery, this doesn’t offer much reassurance.
In my opinion, the advantages of plasmids mentioned in the paper could also apply to viral vectors.
So, Where Do I Stand? Both viral and plasmid approaches have their place, and the choice really depends on the situation and how the technology evolves. I suspect that in the long term, viral vectors will be the better choice, despite their risks. There’s a lot of work going into custom capsid design, which will allow for specific targeting and immune evasion. I think the idea that plasmid-based therapies are "safer" may be leading to a false sense of security.
That said, I’m definitely flirting with both. Can you ask me again in 5 years? Maybe 10?
What are your thoughts?
Thank you! Hmmm I am excited about the possibility for these therapies, especially in the scope of modular adjustments turning genes on and off without more permanent/unwanted changes. Time will tell.
Back to your initial post. I am intrigued by the TERT and follistatin, would love to see this study replicated. The other paper you mentioned with the multi use cocktail was also compelling, but I thought it was odd they didn't include a longevity specific arm. I suppose that wasn't the scope of their intended study, seems like pretty low hanging fruit though. I don't wanna get too cynical, but I wonder if they DID try a longevity side and things didn't work out too well? Either way, that should definitely be a follow up study.