Good news: two knock-in mouse models of genetic prion diseases – fatal familial insomnia (FFI) and E200K Creutzfeldt-Jakob disease (CJD) – have arrived in Montana under the auspices of George Carlson at McLaughlin Research Institute, and new litters of these mice have been born there.
Several months ago, we started a process of trying to import these two mouse models from Walker Jackson‘s lab in Germany to our collaborator Dr. Carlson’s lab at McLaughlin. Ironically, Dr. Jackson created these models as a postdoc at Susan Lindquist‘s lab at M.I.T., scarcely a mile down the street from us. But by the time Prion Alliance came into being, the mice were already in Europe. Due to various holdups with breeding, import permits and so on, it proved surprisingly difficult to bring any mice back into the States. But at last, the mice are now here.
There are a lot of mouse models of prion diseases, and they all come with pros and cons. One pro of these mice is that they are knock-in, not transgenic, which can make for a more faithful and accurate model of human disease. The FFI mice have the same D178N 129M genotype that causes FFI in humans, and they exhibit almost exactly the same sort of symptoms that humans with FFI do [Jackson 2009]. The E200K mice, whose development was just announced last week [Jackson 2013] exhibit symptoms distinct from those of the FFI mice and consistent with E200K Creutzfeldt-Jakob disease in humans.
An important lesson that the prion field is learning is that many potentially therapeutic compounds prove to be strain-specific. Most recently this was demonstrated by 2-aminothiazoles, a class of compounds highly effective against some experimental rodent strains of prion but wholly ineffective against CJD prions. Ideally, we’d do all our testing of drug candidates against human prion strains from the outset. But the difficulty of getting human cell lines to propagate prions, and the expense of dealing with mice expressing human PrP, have so far made this option impractical.
The fact that these FFI and E200K mice reproduce features of the prion diseases caused by each of these mutations in humans is a good sign that these mouse models really model human disease. The prions produced by these mice must share at least a very similar conformation to that of prions in humans with FFI and E200K, and thus we are hopeful that if we can find compounds effective against prions in these mice, they will translate reasonably well to therapeutic use in humans.
Looking forward, Dr. Carlson has plans to cross these mice with other mice that have bioluminescent transgenes that make it possible to monitor their health status visually day by day [Tamguney 2009]. Eventually we hope that these mice will allow us to test therapeutics that might be helpful for humans with genetic prion diseases, much like our current anle138b study in GSS mice.