Hematopoietic stem cell gene therapy improves outcomes in a clinically relevant mouse model of multiple sulfatase deficiency
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Oh, maybe there is some competition with the variant SUMF1? I don't know what the biochemical shortcomings of that particular mutant are, but maybe it traps substrate and therefore also limits the amount of rescue that is possible.
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occurred
This is a really interesting point. The difference between 'preventing storage accumulation' and 'rescuing the impacts of already having storage accumulation' are definitely worth considering, and I appreciate that you chose a point that is most in line with what happens clinically.
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mice
Nice result! Do you have any idea why the sulfatase acitivity wouldn't be rescued but you can see this dramatic improvement in the downstream product levels? Is this a matter of assay sensitivity, or is something else going on?
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cells
This result is really striking! I wonder if the single condition which was not rescued (panel D) suggests maybe a specific sulfatase that still might be underperforming/underactivated?
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sulfatases
It's intriguing that some of the sulfatase activities plateau below the point of WT, though. I'd be curious to see the different levels of the sulfatases at each expression level of the FGE as well. Perhaps there are fewer sulfatases for some reason?
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integrations
Do you have a quantitative estimate of increase in expression for your lentiviral integrations vs. wild type levels? That might be interesting to see.
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