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How to create Congenital Insensitivity to Pain

Ok CRISPER sounds cool =D i guess it'd be nice if there is an approach that has been tried on humans...
yes some CIP people with broken sodium channel have high internal opioid. And they do not develop tolerance to that :\ ... Do you think using some kind of vector to transfer opioid genes in a human is safe? The dose might have to be massive if trying to get close to CIP tho...
 
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Easier to knock down than to amplify. But the tech sounds like it would be possible. Me..would rather work on fungi. At least
 
Can someone tell me more about using CRISPR to knock down SCN9A? How would it work? It sounds hard, too because SCN9A is expressed in a bunch of places (I think in all DRGs and the brain...?) and not just in 1 small space like an eyeball 8(
 
Hwaa said:
Can someone tell me more about using CRISPR to knock down SCN9A? How would it work? It sounds hard, too because SCN9A is expressed in a bunch of places (I think in all DRGs and the brain...?) and not just in 1 small space like an eyeball 8(
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It isn't possible to do that in a living human, and it is unknown whether it would work in a human embryo.
 
Hwaa said:
Can someone tell me more about using CRISPR to knock down SCN9A? How would it work? It sounds hard, too because SCN9A is expressed in a bunch of places (I think in all DRGs and the brain...?) and not just in 1 small space like an eyeball 8(
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Well, we're firmly in the realm of frontier medicine here, it's true. But I think this thread is inherently in that vein anyway!

For a start, since we're talking about introducing mutations into the SCN9A gene, and not knocking it out, you would need to find a way to activate homology-directed repair (HDR) in non-dividing cells like neurons. There are drugs that look promising for this, or you could knock out genes that are suppressing the activation of HDR. Risky stuff, indeed.

Then we deliver the DNA coding for the Cas9 enzyme and the guide RNA by injecting a lentivirus, or adeno-associated virus, into your brain and DRG. Then you'll be a happy bunny, or at least a non-unhappy bunny. An unfeeling bunny, let's settle with that.
 
Jonneh said:
Well, we're firmly in the realm of frontier medicine here, it's true. But I think this thread is inherently in that vein anyway!

For a start, since we're talking about introducing mutations into the SCN9A gene, and not knocking it out, you would need to find a way to activate homology-directed repair (HDR) in non-dividing cells like neurons. There are drugs that look promising for this, or you could knock out genes that are suppressing the activation of HDR. Risky stuff, indeed.

Then we deliver the DNA coding for the Cas9 enzyme and the guide RNA by injecting a lentivirus, or adeno-associated virus, into your brain and DRG. Then you'll be a happy bunny, or at least a non-unhappy bunny. An unfeeling bunny, let's settle with that.
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Why would you want to mutate SCN9A? The mutations cause NaV1.7 sodium channels (which contain the subunit) to be non-functional. So to duplicate the illness you would knockout the SCN9A gene.

To say the least, this is not yet at the stage where it is possible to do this in the human brain.
 
serotonin2A said:
Why would you want to mutate SCN9A? The mutations cause NaV1.7 sodium channels (which contain the subunit) to be non-functional. So to duplicate the illness you would knockout the SCN9A gene.
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If it's truncated and completely non-functional, then sure. That makes our lives a little bit easier.

serotonin2A said:
To say the least, this is not yet at the stage where it is possible to do this in the human brain.
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With high risk, I would assert that it is. What are the obstacles, safety considerations notwithstanding?
 
Like what kinds of high risks? I mean I'd like to try it but if it ends up not working very well, l don't want to get f*cked up in the process and become incapable of pursuing other ways to become an unfeeling bunny :!
 
No ethics board would ever approve this, hospital/university or otherwise, which means you'd need to find someone willing and able to do it without asking a lot of questions. It's also never been done before, so the risks are effectively unknown, and the chance of success is as well. We don't really have an intimate grasp on how the human genome works - we're still at the level of blindly knocking out homologous animal genes and deriving information from that, AFAIK. If the word got out I would imagine the sanctity-of-life crowd would have a field day with the news, too.



(I'm sorry)
 
I believe there is a team working on antagonists for this particular sodium channel, with one Waxman being a researcher on the team (have yet to look into it).

There is also the work being done to develop "addictionless" opoids by Zadina, I believe a study was published in Neuropharmacology in 2015? Have yet to look into that either. I have a feeling there will be a catch.
 
Hm why do have such grave misgivings about (especially) lentiviral vectors....

Funny, that. Who doesn't want a cousin of rabies virus floating around their CNS:p

Whilst some of these novel subtype/splice variant/functionally selective (biased agonists)/MOR-DOR bivalent ligands etc. are pretty interesting, theres just this part of me that thinks 'well didn't they say the same about heroin, as a nonaddictive treatment for addicts to morphia.'
 
Hwaa said:
Like what kinds of high risks? I mean I'd like to try it but if it ends up not working very well, l don't want to get f*cked up in the process and become incapable of pursuing other ways to become an unfeeling bunny :!
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Previous attempts were associated with fatalities. In addition, these procedures require injections to be made directly into the brain and spinal cord.
 
theres just this part of me that thinks 'well didn't they say the same about heroin, as a nonaddictive treatment for addicts to morphia.'
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when heroin was developed and marketed nobody knew anything about its binding coefficients or what receptors it hit or didnt - considering that they missed the fact that it's a prodrug it just goes to show how far we've advanced!
 
Sekio-definately.

Even then however it would have been easy enough to test for physical dependence liability. And psychological for that matter. Even though before the advent of genetic science we couldn't have unravelled the difference between morphine and H in terms MOR splice variant selectivity. And would doubtless have been tricky to have found out the receptor binding profile if doing so in addicts to morphine (and other opioids?) seeing as how H switches selectivity in morphine-tolerant users from being a MOR agonist to primarily DOR agonism. Forget which subtype is targeted by which drug now but 6-MAM and H are selective in these circumstances for DOR1 and DOR2
 
Nope. There's no drug that is selective in that fashion, partially because sensory neurons are just as much a part of your nervous system as any other nerve tiissue. Anything that kills neurons generally will be either non-selective or have toxicity dependent on its transport into the cell (e.g. MPTP) - in which case the expression of various transmport protiens will be the factor that determines which cells die, not a higher phenotypical quality such as being needed for a specific task.

This is getting merged with the thread you linked as it's not any different of a question.
 
sekio said:
Nope. There's no drug that is selective in that fashion, partially because sensory neurons are just as much a part of your nervous system as any other nerve tiissue. Anything that kills neurons generally will be either non-selective or have toxicity dependent on its transport into the cell (e.g. MPTP) - in which case the expression of various transmport protiens will be the factor that determines which cells die, not a higher phenotypical quality such as being needed for a specific task.

This is getting merged with the thread you linked as it's not any different of a question.
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The specific neuron does not necessarily only need to have specific transport mechanisms such that it is selectively vulnerable to certain neurotoxins. More generally, the neuron simply needs to be specific. What I mean by this is that the neuron differs significantly in some way from other neurons, and this difference could lead to vulnerability. For example, NMDA antagonist neurotoxicity occurs in the posterior cingulate cortex and retrosplenial cortex, specifically. One theory is that GABA interneurons projecting onto these cell bodies express NMDA receptors that, when blocked, inhibit GABA release onto these areas and thus disinhibit the RC and PCC. They become overactive and this results in toxicity. If the GABA interneurons did not selectively express more NMDA receptors, or if the RC and PCC cell bodies were not so prone to damage due to overactivity, then NAN would not occur. So in general, any protein that is selectively overexpressed in a neuron could make it more vulnerable than other neurons.

Of course in practice it is often found that a neurotoxin can damage many types of cells, because the mechanism of toxicity involves a common feature of the cells.
 
I've always wondered about a reversible or psueoirreversible ligand being trafficked up into the terminal a bit when it is recycled, and then this happens to be a toxic ligand, fitting into a receptor that is only expressed in sensory neurons. Obviously an extremely long shot and just hypothetical lol.
 
I've always wondered about pseudo-irreversible ligands. Such as rivastigmine, although in this particular, 'aging' makes things somewhat different being that initial binding then results in rearrangement but what ARE PSI-/quasi-irreserversible ligands?
 
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