Novel gene therapy curbs schizophrenia symptoms - UT Health San Antonio

This woman was part of the stem cell therapy research with Dr Lodge. The article above is not written by someone who understands the research - I’m quite sure the scientists involved never said anything about delusions in rodents.

Fortunately the actual paper is public. In it she describes the therapy and how they used it to identify the brain circuits that could be modulated to normalize dopamine activity (positive symptoms) and how their therapy also fixed one aspect of cognitive dysfunction, extradimensional set-shifting, but not reversal learning.

Unlike reversal learning, we found that gene therapy to over-express the α5 subunit of the GABAA receptor improves schizophrenia-like deficits in extradimensional set-shifting as measured by the attentional set-shifting test…
This deficit was completely abolished in the animals that received gene therapy to over-express the α5 subunit in pyramidal cells of the vHipp.

This experiment did not address negative symptoms and the researcher seems to think they have a different neural origin.

In the current experiments, we focused on pathways from the vHipp to the NAc and mPFC. However, schizophrenia is a heterogeneous disorder and the vHipp is not the only site of pathology. For example, structural and functional changes have also been observed in the thalamus of schizophrenia patients59 and we have recently demonstrated that the paraventricular nucleus of the thalamus can also regulate dopamine signaling via the NAc60. Further, the vHipp sends and receives many projections to and from other brain regions beyond the NAc and mPFC. For example, reciprocal connections exist between the basolateral amygdala (BLA) and vHipp61 and optogenetic inhibition of this BLA-vHipp pathway has been shown to decrease anxiety-like behavior62 and increase social interaction time63, which has been used to model negative symptoms of the disorder. Conversely, activation of the pathway increases anxiety-like behaviors62 and decreases social interaction time63. The BLA has been implicated in schizophrenia64, therefore, it is likely that changes in this neural circuit may also contribute to the pathology of schizophrenia.

Full Paper: https://www.nature.com/articles/s41467-019-10800-1#Fig1

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Great news. Gene therapy would be on the market in 10 years probably. Gives hope.

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For now, they’re focusing on what circuits to target for better drugs - but maybe they will go for an actual gene therapy.

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What about chromosome 22?

There’s hundreds of genes on chromosome 22 that make protiens, and I guess probably many more that don’t.

What’s so interesting is that this research used a MAM model, where they give a toxin to pregnant rats or mice at a specific time in gestation. These were not rodents where they knockdown one specific gene and then restore it. So this toxin has a variety of effects that are similar to effects seen in schizophrenia. And then they

use viral-mediated gene transfer to restore inhibitory signaling in the vHipp by over-expressing the α5 subunit of the GABAA receptor in pyramidal cells. We found that α5 overexpression increased tonic GABA currents and normalized aberrant pyramidal cell activity in the vHipp.

Just that one subunit just in pyramidal cells just in the vHipp.

So they’re getting down to very specifc targets and finding which cells and circuits correspond to which symptoms.

With a therapy like this you might not have to know what kind of mutations led to someone’s schizophrenia, or if it was prenatal problems, if those problems affected the pyramidal cells of the ventral hippocampus, something like this might substantially normalize the dopamine system. In this experiment it also restored one aspect of cognition. In rodents.

They’ll have to continue experiments on different circuits for different symptoms.

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