Jim Mastrianni’s lab at University of Chicago has just published its finding that rapamycin (otherwise known as sirolimus or Rapamune) delays disease onset in a mouse model of GSS.  The full paper: Cortes CJ, Qin KF, Cook J, Solanki A, Mastrianni JA. 2012. Rapamycin Delays Disease Onset and Prevents PrP Plaque Deposition in a Mouse Model of Gerstmann–Straüssler–Scheinker Disease. Journal of Neuroscience 32(36):12396 –12405. [full text]

The authors had at least three good reasons to think rapamycin might work to delay GSS onset.  First, it inhibits mTOR, thereby promoting autophagy, hastening the clearance of “aggregation-prone” proteins.  Second, it’s been shown to be helpful in experimental models of all four of the other big neurodegenerative diseases: Parkinson’s, Alzheimer’s, Huntington’s and ALS:

Numerous reports describe protective effects of rapamycin in cell, fly, and mouse models of several neurodegenerative diseases that result from accumulation of misfolded aggregate-prone cytosolic proteins, including Parkinson’s disease (PD) (Webb et al., 2003), amyotrophic lateral sclerosis (Fornai et al., 2008), Huntington’s disease (HD) (Berger et al., 2006), spinocerebellar ataxia Ravikumar et al., 2002, 2004), and frontotemporal dementia (Williams et al., 2006). Despite the lack of cytosolic aggregates in Alzheimer’s disease (AD), autophagy appears to play a complex role in Aβ production and clearance, and recent work suggests a beneficial effect of rapamycin in some AD mouse models (Nixon, 2007; Spilman et al., 2010; Yang et al., 2011).

And third, autophagy drugs have been shown to be possibly-helpful in variant prion diseases, though not yet tested for genetic ones:

Pharmacologic induction of autophagy appears to promote the clearance of PrPSc in vitro (Heiseke et al., 2009a,b), and a limited number of in vivo studies have found either no effect (Sarkar et al., 2007) or a modest effect (Heiseke et al., 2009b) to prolong survival following scrapie infection. However, whether autophagy induction can delay the development of genetic prion disease has not been addressed.

Based on this, the authors decided to test rapamycin on GSS model mice.  Mastrianni’s group had already created this line of mice for an experiment a few years ago; they were first documented in Yang 2009.  A bit about that mouse model: Yang started from a homozygous Prnp (note: Prnp = mouse gene, PRNP = human gene) knockout line of mice created at the Prusiner lab, the Tg(Prnpo/o) line.  Yang then introduced a new copy of Prnp bearing the GSS-causing A117V Update 2012-09-14: A116V (equivalent to A117V in humans, see comments to this post) mutation into pronuclei of this knockout line, bred hemizygous Prnp A117V A116V mice, and demonstrated by biochemistry, histology and observation of clinical phenotype that these mice faithfully recapitulated human GSS symptoms.

I’ve summarized the results in the table below.  The delay in disease onset for 10mg and 20mg mice works out to 10% and 18% respectively, so in human terms, if you were going to get GSS at age 40, you’d get it at 44 or 47 instead.  The delays in onset are significantly different from control but not from each other (ANOVA with Bonferroni correction); the extension of lifespan is significantly different only for 20mg mice.  The authors also found some evidence that, even after onset, the treated mice had less severe symptoms (see their Figure 2).

Dose Average age at disease onset Average age at death n
Control 134 days 173 days 17
10 mg/kg body weight, 3x/week 149 days 175 days 25
20 mg/kg body weight, 3x/week 159 days 189 days 20

Along with all this, the paper draws some interesting conclusions from histology and biochemistry on the mice.  Most notably, the 20mg mice evidenced no amyloid plaques whatsoever; the fact that they nevertheless eventually developed symptoms and died of GSS indicates that the plaques are not essential for pathogenesis.  Of course, the major take-home from this paper is that rapamycin has potential therapeutic value for genetic prion diseases.  That’s exciting.  But even besides the fact that this is just a mouse study, there are also a few other reasons to be cautious.

Rapamycin is a serious immunosuppressant prescribed to prevent organ transplant rejection.  Its side effects include impacts on the lungs, platelets, cancer risk, and a host of other things according to Medscape [adverse effects/warnings].  Moreover, the doses used in this study are enormous.  20mg/kg, 3x/week works out to something like 450-650mg/day for most people.  UPDATE 2012-09-14: The doses used in this study are fairly large; based on body surface area (BSA) conversion from mice to humans, the 10mg/kg and 20mg/kg 3x/week doses work out to about 24 and 48mg/day for a 70kg person.  (See discussion in comments below this post.)  A typical dose of rapamycin used for immunosuppression with organ transplants is just 3mg – 15mg/day according to Medscape.  There is some suggestion in the literature that the dependency of rapamycin’s effects on its dosage may be fairly complicated [Foster 2009], though it’s not clear, to me at least, what that means for this study.  Finally, the mice started the drug at age 42 days, which is equivalent to just a few years old in human terms.

Rapamycin is kind of scary stuff, but it’s also got a pretty fascinating track record of extending lifespan even in wild-type organisms.   Harrison 2008 [supplement] showed lifespan extensions of 9-14% in mice on rapamycin, even starting the treatment at age 600 days, which the author equates to 60 years in human terms.  MIT’s Technology Review did a nice writeup of the implications of this study.  It followed on the heels of studies showing that reduced TOR pathway activity extended lifespan in yeast, C. elegans and Drosophila.

As of today, rapamycin is an expensive patented drug owned by Wyeth.  Medscape lists a price of $23/mg, and sites with far lower prices seem to be selling it as a chemical, not a drug [1][2].  Good news is, the patent expires in June 2013.  I learned a tidbit in the process of trying to figure this out– the FDA didn’t actually approve rapamycin until 1999 , but (as Wikipedia’s page on generic drugs explains so eloquently):

In the US, drug patents give 20 years of protection, but they are applied for before clinical trials begin, so the “effective” life of a drug patent tends to be between seven and 12 years.

And in fact, as early as 2008 Ezra Cohen at UChicago editorialized that this is a good reason why researchers should be interested in rapamycin as a cancer drug:

There is one other compelling reason to develop rapamycin for cancer patients that is far removed from biology, but is no less important. At doses currently utilized, it would cost approximately $1,000 per month to treat a patient, but the cost could decrease dramatically when the patent for rapamycin (US patent #5,100,899) expires in 2013. With patent expiration looming and the time required to garner approval for an oncology indication, it makes little financial sense for the current manufacturer to develop rapamycin for cancer therapy, especially when the patent for rapamycin use in malignant disease has already expired. Without patent protection, there is little commercial incentive for the private sector to develop the agent. However, this is a situation in which public or philanthropic intervention would yield substantial long-term savings when one compares the price of conducting clinical trials against escalating nongeneric drug costs.

The subject of Cohen’s article was the amount of energy being poured into trials of other new drugs which interfere in the mTOR pathway (temsirolimus, everolimus, and deforolimus). Today we can add to the list Novartis’ BEZ235 and others as well.  While these drugs will remain expensive for a longer time (if they even achieve approval), these are also potential candidates to test for therapeutic value against prion disease.  By showing that rapamycin is effective at delaying disease onset, albeit at a very high dose, Cortes and Mastrianni have not only shown us a potential therapeutic, they’ve also confirmed our suspicion that autophagy is one druggable path to prion disease treatment and have given us reason to be interested in the mTOR pathway more broadly.