WHG
(Sorry about the delay)
Regarding the potentialbenefit of using rapid for gene therapy: recall that Gelsinger received trillions of virus particles. The dose was undoubtedly the result of prior testing, the response of previous subjects in the study, and Gelsinger's condition/constitution. However, it is my recollection that the dose was well within the range of safety established via prior patients in the study...where the immune response was consistently minor (caveat: the NIH did uncover numerous violations of protocol in Wilson's lab and I've not read these findings. Thus the 'minor' immune responses may have been more significant).
In hindsight it is clear that Gelsinger's liver status contraindicated implementation of the therapy. It is possible - and I stress this is pure speculation - that a lower viral titer could have either avoided the immune response altogether or diminished it to the degree that the outcome was altered.
How might RAPID play a role?
The expression cassette used for Gelsinger was constitutively driven and produces 'X' amount of gene product. Let's assume, for this discussion, the inducible promoter in the RAPID construct produces the same level of therapeutic protein when 50% induced. Let's also assume that this level of circulating gene product represents the midpoint of a range assumed to be appropriate for any given individual. If Gelsinger had received an order of magnitude fewer viral particles (containing RAPID), and gene expression was then titrated 'de novo' with oral rapamycin (or Ariad's analogs), perhaps a lower level of circulating gene product would have been completely sufficient. There's no means to titrate gene dosage from a constitutive promoter....other than testing many viral titers (which is impractical at best). I don't recall the range of circulating gene product driven by differential induction of RAPID (as reported in the Science article) although I believe it was at least 100-fold. Of course there is always the possibility - even the likelihood - of insufficient dosing at the lower viral titer (even if RAPID is maxed out), but the ability to perform on-board titration of expression suggests a compelling alternative to immune response towards overwhelming viral loads.
I fully appreciate that there is more speculation here than hard science. I would also stress that RAPID is hardly a known entity and this scenario may be completely inappropriate. Again, RAPID may not be able to deliver sufficient protein in this, and other, GT models and the range of inducibility of RAPID may be insufficient to compensate for a meaningful drop in the viral dose. Moreover, if finely crafted AAV, lentiviral, or other vectors are shown to be CONSISTENTLY non-immunogenic, this rationale for using RAPID would be reduced.
Prior to Jesse Gelsinger, Wilson had treated numerous patients in a similar manner. While the range and severity of side effects in these earlier subjects appears to be in dispute, this was the first death directly linked to GT. The abuses of protocol certainly clouds a completely straightforward understanding of this event. Gelsinger's outcome does indicate there continues to be individual factors determining specific responses to massive viral loads. This suggests creative approaches to reducing virus-associated risk in GT should be evaluated. |
