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I'm reading "Highly efficient endogenous human gene correction using designed zinc finger nucleases" by Urnov et al. They propose a way to use zinc finger proteins for gene therapy. They repeatedly claim their method is "selection free" and it seems they are claiming that as an advantage to their method.

Why would selection free be an advantage? Wouldn't you have to select for the transformed cells anyway to be relevant in a clinical setting?

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Urnov et al. are trying to effect gene therapy - where a mutation causing a genetic form of severe combined immunideficiency (SCID) (also known as the bubble boy syndrome). Affected SCID patients can have little to no immunity to infection what so ever. SCID in this case is caused by a single site mutation in the IL2R-gamma gene.

Their method is to use a DNA binding protein (containing zinc finger domains that bind the DNA) which attracts a DNA repair enzyme.

The result is that 18% of the cells have the SCID gene repaired. This would have been a trivial result if they had applied selection, which generally refers to any method which eliminates cells which were not affected (in this case having their DNA repaired) by a transformation like their treatment. They claim that 18% of all the cells were repaired (I assume this is in a cell culture). This implies that if their treatment were applied to living tissue, 18% of the cells would be repaired in situ, which should be enough to restore immune function.

While its possible to apply a selection method to gene therapy, it would be far better if you did not. Cancer chemotherapy for instance is a selection based treatment for instance, relying on toxins which kill fast dividing or growing cells preferentially, leaving the slower growing tissues relatively viable. Still its quite toxic and disruptive to the patient.

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-1. "This implies that if their treatment were applied to living tissue, 18% of the cells would be repaired in situ." Not at all. If only it were true that findings in a dish could draw such a straight line to results in the body! – yamad Feb 1 '13 at 15:43
i used the word 'implies' for this reason. I think this is a Nature article because they have suggested this very thing. They are trying to demonstrate potential for in vivo gene therapy without selection as far as I can see. – shigeta Feb 1 '13 at 21:36
I agree that they are trying to demonstrate a method that will be applicable for in vivo gene therapy. The results are suggestive of some rate of efficacy for in vivo repair. However, an 18% fraction of repaired cells in a dish does not point to, or even imply, an 18% fraction of repaired cells in a body. – yamad Feb 2 '13 at 23:51
I'm sure most would agree with that. Gene therapy has been an extremely difficult idea to realize in practice. So much so that what is a preliminary result like this is published in a top tier journal. This is promising, but far from a resolved problem. It would be a strong contender for a Nobel Prize in Medicine if it did turn out to be a real treatment for SCID. – shigeta Feb 3 '13 at 0:29
Thanks shigeta - this makes it very clear. I understand yamad's point, but I also get that this points to a possibility that some non-trivial amount of cells could in theory get transformed if this treatment were developed in situ. So this does mean, right, that this treatment could only be applied to cases where cells are deficient in some manner or have some loss of function. If the cell were to gain some active malfunction - repairing a small proportion of the cells may not actually have a great impact. Would you agree? – SimaPro Feb 13 '13 at 6:07

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