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Yes, I saw that case. It seems that they were using an extremely high viral dosage. In my understanding one of the reasons AAV is typically used is the low immunogenicity at normal dosages and overall good safety profile. Obviously no pioneering method is without risk.

Whether mood disorders qualify under your criteria is debatable - certainly for a large proportion of people no currently available treatment is effective. Fatality rates may be relatively low, but I suspect a fairly large cohort of people living with mood disorders would rather tolerate some risk than live out the rest of their lives with no hope of treatment.

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Gene Therapy for Mood Improvement

by Ray Allen

Jan 11 20231 min read 8

7

BiosecurityPhilosophyBiotechnologyDavid PearceWellbeing

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Hi everyone,

I've had an idea for a few years that I'd like to start moving towards trying to implement. It's inspired by David Pearce's Hedonistic Imperative.

The idea is to sketch out a detailed road map for developing an in vivo gene therapy for mood improvement. It seems like the essential technology for this now exists, but I haven't seen any sign of anyone working practically on this specific problem. Presumably some day some big biotech company will take this on, but I'm curious whether some enthusiastic amateurs can make any meaningful progress. Things like:

- Fleshing out the technical theory of a therapy. I'm thinking AAV-based, but open to other ideas. What specific viral (or other) vector variant to use, what promoter, what transgene to try, how to deliver to the target brain area, potential side effects, etc. Eventually aiming towards a fully designed viral vector code, with delivery method.

- Thinking about testing. Assume we think we have achieved the previous step. Without the backing or budget of a major lab, how difficult is it to carry out animal tests? Could it be done somewhere in the world with sufficient scientific standards but lower cost and/or regulatory barriers?

- Ultimately human testing will be the end goal, this is well down the road and probably the most challenging aspect but still worth thinking about.

Rather than thinking in terms of attracting capital, licensing, commercialization etc, I want to focus on establishing a working therapy, though of course some capital would be required to get anything done.

I have some ideas about these things of course, but would like to get more brains involved if there is interest. For example, I lack the expertise to bridge the gap between designing a viral vector and having something physically ready to administer to an organism.

Alternatively if anyone knows anyone who's already working on a similar project I'd appreciate being pointed in the right direction. I'm already in discussion with someone from a project with similar aims but focusing more on germline therapy.

Please comment or PM me if interested or have questions!

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Lila RieberJan 11 202317

I work in gene therapy and can tell you that it has huge risks, which means that it's mainly considered for diseases that have no other treatment and would otherwise be fatal. For example, the latest gene therapy trial for X-linked myotubular myopathy has had four children die, probably because of AAV toxicity. The reason gene therapy is being considered for XLMTM is because it involves loss of function of a single gene in a specific cell type, as well as meeting the criteria I said before. Mood disorders aren't good candidates for gene therapy.

Ray AllenJan 12 20232

SabsJan 11 20235

isn't this a little bit optimistic given the massively polygenic nature of depression?

Ray AllenJan 12 20232

Definitely there's no single gene that controls mood, I think it's agreed that it's a combination of many factors, genetic and otherwise. But, strong correlations do exist between some alleles and subjective wellbeing. 5-HTT and FAAH are two genes with such alleles, off the top of my head.

SabsJan 12 20231

pretty sure that's all stuff from the candidate gene era that didn't replicate in GWAS. Population structure is a real bitch unfortunately

Ray AllenJan 12 20232

Did GWAS collect data on subjective wellbeing? I have seen that they have some data on severe mental disorders, but that's not the same thing. I have wondered before about trying to collect a genomic database along with self-reported mood data, I think that would be massively useful, if it's been done I haven't seen it.

One-time padJan 11 20231

Depression =/= low mood. Its just one of a plethora of ways to have sustained periods of low mood. The real question is how larger proportion of mood is determined by the top genes

Pigeonfan93Sep 9 20231

There is a company that's working on this or at least on similar things like this. They're called Cognigenics and they released a paper some time ago that was very well received as far as i know. They invented a nasal spray that seems to be capable of crossing the blood-brain barrier and they used it to genetically change the brains of mice. The mice showed less anxious behaviour afterwards.

I'm neither a geneticist nor a neuroscientist so i can't say much about it. But i too really hope that things like this will become a reality. I have suffered from severe mental/neurological problems from a young age. I have very little control over my emotions and suffer a lot because of it. I think my medication helps a little bit, but not very much. It would be my dream to have a healthy brain that actually helps me to be happy and not miserable/scared.

Sorry if my english isn't perfect.