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A Cautionary Tale.https://www.sciencemag.org/news/2020/01/virus-used-gene-therapies-may-pose-cancer-risk-dog-study-hints In a nutshell: In 2 out of 9 dogs and after 5 years or so, fragments of the AAV delivered new gene broke off and integrated itself here and there in the native DNA genome. It seems the only problem integration was near a growth determining part of the DNA - causing excessive replication and forming a small harmless mass. In other insertion areas it just happily kept the gene therapy going strong instead of slowly fading as cells replicated. So that was judged a plus of the phenomena. But then some wondered, what if these dogs had lived another 5 years more? - perhaps even that could get out of hand. Human patients now at 9 years being dosed with a hemophilia GT are about to have their livers biopsied to see if it might be occurring in them as well. And a new 9 dog study is being done to analyze just this phenomenon. So. Probably this shouldn't impact our current GT candidates. It's too rare and somewhat benign an occurrence as yet. And I suppose it even depends on what kind of "fragments" break off or don't break off in any given gene replacement gene being used. So it's a small window of concern I think. But if one were to imagine a future of hundreds of AAV delivered GTs....well, at that point, lots of nutty stuff could occur ...and who's going to want that uncertainty in a possible future mega industry? No one. That's why we are already exploring many other approaches, I imagine. Stupid to put all your eggs in one basket. Gene editing. Other delivery mechanisms - if that means anything here. PPMO, and on and on. But also the PPMO comes into play not only as an alternative to GT - and not just for the current DMD program. But a PPMO could be used to "counter" or "silence" any kind of over production that the rogue fragments might wreak in the genome, if it gets in. For example, what was seen in two of the nine dogs above! You identify it, target it, and suppress it so it doesn't create TOO MUCH of a given protein....or any other problem a random rogue fragment might be causing. How 'bout them apples?! So if any GT shows a problem such as seen in the two dogs, you identify the imbedded fragment, design a PPMO to go in and knock it out - to the extent you want it knocked out. So in addition to a GT engine, Sarepta could also develop a "GT fine tuning or correcting" engine. Thus saving "traditional, as-it-stands-today Gene Therapy. We ought to get access to the 9 additional dogs being studied in response to this previous 9 dog study, and start doing the work of developing a "corrective PPMO" that we could then ask to treat any dog that might develop the same problem in that current study soon to begin. My Mom never should have read me that Dr. Seuss book as a kid, I guess: If I Ran the Circus! https://en.wikipedia.org/wiki/If_I_Ran_the_Circus |
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