Adult reversal of cognitive phenotypes in neurodevelopmental disorders

Doesn’t mention schizophrenia directly but does mention DISC1 (Disrupted in Schizophrenia1)

There are now a number of compelling examples, in mice, of rescue of neurocognitive deficits associated with developmental disorders in adults , including NF1, TSC, Down syndrome, Rubinstein-Taybi syndrome (RTS), Fragile X syndrome (FXS), and Rett syndrome.

This part is about Rett syndrome:

The analysis of a number of phenotypes caused by the Mecp2 mutation, including hind limb clasping, inertia, irregular breathing, gait, and tremor, showed that these phenotypes were not irreversible even in adults. Accordingly, restoring Mecp2 expression in mature female mutant mice, after onset of neurological disease, reversed function to wild-type levels and restored proper levels of neuronal plasticity. Interestingly, sudden restoration of Mecp2 function actually caused death in half of the mice treated, while a more gradual re-expression schedule did not. This result suggests that the dynamic (although precarious) biochemical balance established in mutant mice had to be reversed in a progressive gradual manner. Additionally, it is important to note that restoration of normal Mecp2 expression only took place in approximately 80% of cells, demonstrating that complete reversal is not needed for significant gains in function. This is a key result with significant repercussions for possible future clinical studies with viral vectors where only a subset of cells may be expected to be transfected. These fascinating findings demonstrate that deficits caused by loss of Mecp2 function in development do not result in irrevocable impairments.

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The reason I was posting this is the discussion of gene therapy and how long that might take to develop. Rett syndrome is a known single genetic defect, so the target is known. They’ve been working with turning a copy of the gene back on for a couple of years now in mice.

(This paper is actually 10 years old, but the method they used wouldn’t be practical for people, but CRISPR is, and they’ve been using that in mouse models of Rett’s since 2016.)

So I think we will get an idea of the timeline to translate that into people. It will probably be pretty big news when they start recruiting for a clinical trial for gene therapy in Rett’s. I think it is very likely that it will be tried in toddlers first. Eventually they may try it in adults. Another disorder to watch for gene therapy is Fragile X.

So then we might have an idea of translation times for other neurodevelopmental gene therapies. That might be shortened a bit since it won’t be something they’ve never tried in humans before and they can apply what was learned in applying it in single gene developmental disorders.

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