I don't know if there's still an active cell line in the lab, but have they tested 1-deoxynojirimycin, or nojirimycin? Although they're glycosidase inhibitors, since this is a lysosomal storage disease, IIRC one copy of the NGLY gene is dead because of a nonsense mutation but the other has an uncharacterized, non-catalytic mutation. This one might be rescuable through a "chemical chaperoning" effect, ironically the proper treatment then is an inhibitor to the enzyme you're trying to save.
Relevant research on a (beta-) glycosidase (but presumably the active site structure and thus the inhibitory mechanism of nojirimycin should be similar):
Also I had a short discussion with Dr. Freeze about his results showing that flooding with mannose (not therapeutically viable) improves activity, mannose is a weak NGLY1 inhibitor.
Also Mz: I was the biologist that responded to your query!
Matt: I'm on temporary hiatus from science work and have a lot of flexible free time, and am located in San Diego, where I know some of the work has been done. If there's a lab that has access to relevant cell lines, I'm willing to do a bit of work here and there on a volunteer basis to try and explore a therapeutic strategy, have some ideas to quickly ascertain if the chemical chaperone route is wise or not, especially if they have a working assay going.
N-Glycanase 1 plays an important role in deglycosylating misfolded proteins, allowing them to be recycled into their constituent amino acids.
Bertrand's cells appear to be accumulating misfolded glycoproteins.
And I went back to my own research notes. And basically, even if you can't yet fix the defect, you can probably improve the cell ph balance and salt/mineral balance to reduce the incidence of misfolds. Since the issue here is that Bertrand's cells cannot take out the garbage, preventing the accumulation of garbage would help reduce symptoms. (And this is the essence of how I have reversed a lot of my symptoms: I initially thought I would be on high levels of supplements for life but correcting the cell chemistry has put a stop to the "normal progression of CF" and maintaining good health has turned out to be way easier than the battle to get here. YMMV, and probably will. For Bertrand, this is more of a stop-gap measure.)
Anyway, I thought I would toss that out there as something you might consider looking at -- as something that might get immediate therapeutic results, well before the FDA etc will ever approve anything likely to fix the genes.
Sanford Burnham is in San Diego and is the leading lab for NGLY1. All of the cell lines for all of the patients are there. Dr. Freeze has a variety of assays related to NGLY1 available.
It's really amazing to watch things like this happen. I wish I knew something I could do to help, but the closest I can come is having used Pygr exactly once.
We'd been considering N-acetyl-dideoxy-nojirimycin (2-ADN) to inhibit a different enzyme related to NGLY1. (I can't discuss more publicly since the research is unpublished, but would be happy to discuss over email.)
Can you explain a little more about how an inhibitor for NGLY1 could rescue the frame-shifted (non-nonsense) variant?
the inhibitor to NGLY1 would not be able to rescue the frame-shifted variant, it might be able to rescue the other variant, under certain conditions, unless that variant knocks out the active site (I can't remember from the original manuscript if it does or doesn't, and I can't seem to find it). Sorry for the lexical confusion.
Also, on re-reading the description of NGLY1 (it's been 2 years) I realized that an acetyl-nojirimycin might be a better choice! Looks like my intuition was correct.
My memory of the discussion is fuzzy, but I talked a bit for a couple of days with this biologist and then I wrote a long blog post with my thoughts. My recollection is that my conclusion was that due to the way that NGLY1 works, Bertrand should be deficient in a number of proteins that work as, among other things, cell channels, including but not limited to the CFTR, which is the one involved in CF.
So it seems to me he should have some of the same issues, like specific deficiencies, high acidity, etc.
In fact, the first ever treatment we tested in the lab was a read-through compound often used to treat some forms of CF: gentamycin.
It didn't work for Bertrand, but it may still work for other NGLY1 patients.
Phenotypically, there are some overlaps with NGLY1 and CF, so there may be commonalities in the underlying mechanisms of harm.
I'll ask the NGLY1 researchers what they think about a CF-NGLY1 link.