March 27th, 2023
Here's update #3 on LEVF's "round 1" attempt to achieve robust mouse rejuvenation!
Yesterday we started the treatment of cohort 3, which consists of 200 mice, 100 of each sex. The two treatment groups within this cohort are numbers 4 and 6 in the project description, respectively receiving:
only telomerase
senolytic, telomerase and HSCs (so, not rapamycin)
As a reminder: we don't do all the therapies at the same time, partly because of stress on the animals and partly because of our intuition as to how they will most productively interact. In particular, we have decided that the telomerase gene therapy will be administered last, after completion of the HSCs and senolytic regimens, because we don't want to risk the possibility that telomerase will temporarily "de-senesce" (hence, render resistant to the senolytic) cells that we want the senolytic to take out. So while this cohort includes the first group to be receiving mTERT therapy, it will be some time yet before the virus is actually administered.
Other than that, there's not much to say about cohort 3. However, I do want to mention a tweak that we've made starting with cohort 2. In my last update I mentioned that we had seen three deaths in cohort 1 that we felt might have been caused by the senolytic vehicle. We worked very hard to analyse the problem (even though it was only three mice), and we came to the conclusion that one possibility was excessive stress caused by so many injections in quick succession, because the deaths were all in the "mock" subgroups rather than "naive", i.e. they were receiving sham injections.
So for cohorts 2, 3 and 4 we are inserting a two-week gap between HSC and senolytic. With the nicely large number of mice we're working with, we'll be able to discern with good statistical power whether this made a difference. However, we anticipate that if there really was a problem with cumulative stress of the two treatments, it will have been transient, i.e. all the mice that got the senolytic immediately after the mobilisation and survived will recover and be just as healthy a month after treatment as those that got the two-week recovery period. Let's see!
The only other thing to report is that last week we had some hardware problems which limited the number of HSCs we were able to purify per day. But the Ichor team brilliantly coped with that in a manner that has meant no consequence for the overall experiment other than shuffling a few mice between treatment groups. Three cheers for Ichor!