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Biotech / Medical : ARIAD Pharmaceuticals

ARIA 23.99

0.0%

Feb 17 4:00 PM EST

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To: Pseudo Biologist who wrote (1006)	2/7/2000 9:35:00 AM
From: scott_jiminez	Read Replies (1) of 4474

...a topic brought up earlier in this forum Indeed Message 12783041 . I'm beginning to think that since Ariad exhibits such an ability to innovate, they may just be able to implement my idea of creating an insulin construct with a GRE replacing the FKBP element. That certainly would match Furlanetto 's desires. Nevertheless the guy does come across as wanting to skip all the steps between a model T and interplanetary travel. You are correct in noting that the dimerizer was given iv. I had forgotten that this was also the case for the primates in the 1/99 Science paper. The exact quote from the paper regarding oral dosing is, Similar results were obtained upon oral administration of higher doses of AP22542. A bioavailability of 20% may not be anything out of the ordinary...perhaps a pharmacologist could help us here. It would seem prudent for the company to begin concentrating on the oral delivery aspect of this system. Regarding the 'luxuries' of the system, yes, though there appear to be even more than you noted. For instance, the authors used 4 repeats of the Fm motif - the CAD formed from mutagenizing FKBP12. A 4 repeat produced tightly bound aggregates which were virtually non-leaky in the absence of the dimerizer. However, they did a titration of 1 to 4 of these CADs and found a very high correlation to leakiness (Fig. 4., 1 CAD being very leaky - constitutively producing ~2/3 the level of insulin to that of dimerizer induced). Thus, as the authors point out (emphasis mine), The rate of basal secretion ("leakiness") of the system can also be "tuned" by altering the number of Fm molecules incorporated into the fusion protein (Fig. 4); for example to provide low-level constitutive production of insulin between meals. This is a non-trivial issue (understatement) which (IMO) has been glossed-over in all the press coverage of this report. My impression is that it escaped Dr. Furlanetto's keen radar as well. More later...including a discussion of the Authors' statements 1) that RAPID may be easier to deliver by AAV than transcriptional control systems (i.e. 'classic' ARGENT) and 2) RAPID may be 'useful' for other proteins secreted in short bursts ...such as those associated with pain and weight control. This may be a not-so-subtle hint at the clinical applications Ariad is targeting for RAPID...at this very moment.

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