>>not sure it would make sense if simple withdrawal of the dimerizing drug would effectively shutdown expression, if the system is not "leaky"<<
The lack of leakiness with ARGENT was one of the primary features of this reagent that caught my attention in the first place. This was shown in the Science paper with EPO, and in other studies. For instance, in the mouse/GH report (acrobat: pnas.org the point is made quite clearly: in Fig 2., the difference between a constitutively expressing vector (open circles - AdCMVgGH) and the ARGENT based system (closed circles, AdTF1 + AdZF1) is quite dramatic. Plasma levels of hGH fall below the level of detection upon removal of Rapamycin. The paper also shows the effect of various dosing regimens. In addition, and perhaps the singular reason for spending some time with this paper, is the data comparing nude vs. immunocompetent mice in the context of Ad vs. AAV vectors. The inducibility (and lack of leakiness) of ARGENT in immunocompeptent mice using AAV is shown in Fig. 4.
This last point is consistent with Ariad's news release from Keystone where they reported ARGENT inducibility in non-human primates for at least 1 1/2 years. While there still may be some justification to add the 'failsafe' construct to this system (but since both are ARGENT based, the two FKBP-associated mechanisms would have to be absolutely distinct), I would guess the lack of leakiness would obviate the need for this.
I think it's virtually impossible to predict how ARGENT will run the clinical trials course. This has now become an exceedingly UNCLEAR issue in the wake of Gelsinger's death/Wilson's conduct/IHGT shutdown. In my view, it's been EXTREMELY disappointing that Ariad has been completely mum on this topic....shades of old Bergeresque behavior that appeared to be evolving into a more open, candid approach.
OTOH, I continue to believe that the clinical programs, whether ARGENT-GvHD or other ARGENT-based in vivo applications, may not be the company's most promising source for sustained and substantial income. I believe the licensing of ARGENT for innumerable approaches, both clinical and benchtop, is a much more likely, and certainly an earlier, prospect. For example, as I noted before, in contrast to ARGENT's inducibility, just about every other GT company uses a constitutively expressing system. The advantage of having a 'failsafe' mechanism in these scenarios is so compelling that Fas-ARGENT may produce Ariad's first significant revenue stream.
WHG - I'm not quite clear what you're referring to since I was not at the meeting. It sounds like a) part of the GvHD project where cells from BMT are transduced ex vivo with ARGENT-Fas, 2) part of the FKBP modification process that occurred so that Rapamycin (immunosuppressent) could be shelved in favor of a dimerizer that had no endogenous activity. This latter point has been the rationale in switching over to AP1903, a powerful synthetic dimerizer with no known effects in vivo (this was the basis of Tim Clackson's paper last year pnas.org ).
Best wishes,
Scott |
