7 replies to this topic

[henri]

As far as I'm aware of, Aubrey de Grey has presented two options for introducing xenohydrolases into cells: enzyme replacement therapy (ERT) and gene therapy. The problem with ERT is that one would have to cross the blood-brain barrier, which provides some difficulties. But one cannot transfer genes into all brain cells either. That would be needed in order to get rid of tau (the protein that forms tangles inside neurons). The option that some genetically modified cells would secrete the enzymes into the blood stream to be picked up by others wouldn't help here, as this would require crossing the blood-brain barrier, even if the modified cells were in the brain. This is something I see as problematic and worth some attention. If it has been thought out, then fine.

[John Schloendorn]

This concern is certainly just. There are some ideas on how one might solve this problem, e.g. the use of protein transduction domains (look up HIV-tat or transferrin receptor on pubmed) but all this is not exactly straightforward and needs much more work. It's one of the questions that can't be solved by thinking about it alone. One has to get out and try.

[ag24]

Don't miss Weihong Pan's talk at SENS2 :-)

[jaydfox]

For purposes of effecting escape velocity, the transfection rates would only need to be "good enough", where "good enough" is probably fairly high, but not unreasonably so. After all, we lose brain cells every day, and yet we don't just drop dead: the problem has to build to pathological levels (a theme in SENS). Cut that rate by 90%, and you buy yourself a lot of time.

[henri]

Have you already considered the following idea? Transfer the xenohydrolase genes to bone marrow, with a signal sequence that allows the enzyme to be secreted. Then the bone marrow produces monocytes, which cross the bb-barrier to become microglia, which go to live in between the neurons. The microglia would then secrete the enzymes into the interstitial space, from where they could be taken up by the neurons and transported into lysosomes.

Conveniently, the microglia would spread themselves among the neurons all by themselves, and reach every place in the brain - right?

[ag24]

This is an approach I've wondered about for a while, and I should explore it more. I have been confused by the failure to use such an approach in other similar circumstances -- for example, the ongoing NGF trial headed by Tuszynski uses fibroblasts injected into the brain. Perhaps this concern is misplaced though, as the motivation for that approach may be a concern that NGF might be harmful if secreted into other tissues. But the common theme of these two approaches, namely secretion by one cell type and uptake by another, is definitely valid and I discuss it on my "delivery options" web page (www.gen.cam.ac.uk/sens/deliv.htm).