Today, reading a collaborator’s biosafety protocol for handling prions, I was surprised to see that the procedure for what to do in the event of an accidental cut or a needlestick with human prion-contaminated sharps was no different than in any old non-prion lab:

Squeeze cut gently if bleeding. Over sink, gently but thoroughly wash with soap and water for several minutes. Disinfect cut and bandage if necessary using first aid kit.

This is a much more mild pronouncement than that once given by Adriano Aguzzi and John Collinge at the height of the vCJD epidemic.  Those two suggested that an accidental pinprick with a (human) prion-contaminated needle should be followed by immersion in a strong base or bleach (e.g. 1 N NaOH or 20% Clorox), surgical excision of the site, and oral treatment for two weeks with an “anti-lymphocytic” agent such as prednisone (to inhibit white blood cells from proliferating and localizing to the inoculation site, where they might become infected and then spread the infection systemically) [Aguzzi & Collinge 1997 (ft)].

In the 17 years since that writing, hundreds of researchers and neurosurgeons have worked with prions and exposures have doubtless occurred, yet no known acquired prion infections have resulted, and health care workers do not appear to be at increased risk of prion disease [Alcalde-Cabero 2012].  Meanwhile, the vCJD epidemic has nearly tapered off, with fewer than 200 dead [UK CJD Surveillance] in spite of millions and millions exposed.  Human prion strains, we’ve learned, are transmissible but not highly infectious. Accordingly, scientists’ concern about the risk of accidental prion infection seems to have lessened over time.

The biosafety protocol mentioned above also reads:

Using safe BSL-2 laboratory practices, these agents present a low risk of infection to laboratory personnel. However, should infection occur, the results are potentially lethal with no favorable therapeutic intervention currently available.

Which is unfortunate because, while the ability to treat prion infections of the brain still eludes us entirely, we’ve actually made a lot of progress on treating prion infections in the periphery.

I’m referring foremost to anti-PrP antibodies: peripherally infected mice treated with the antibodies ICSM 18 or ICSM 35 can be completely cured of infection before it ever reaches the brain [White 2003]. One of these antibodies, ICSM 18, has now been humanized as PRN100 and the MRC Prion Unit is interested in launching a clinical trial of this antibody for sporadic Creutzfeldt-Jakob disease. Because the mechanism is PrPC-based – probably stabilizing the native conformation, maybe occluding or promoting release and degradation – it is probably not strain-specific, so there’s every reason to expect that antibodies would work just as well on human prions as on mouse prions. The major obstacle to PRN100′s efficacy in a clinical trial will not be strain specificity, but rather blood brain barrier permeability.

Whether PRN100 will enter the brain in sufficient concentration for therapeutic effect remains to be seen. But if there were currently an epidemic of peripheral prion infections in humans – and if people knew their infected status before neuroinvasion, before symptoms – then I’d be willing to place a bet on longbets.org that such antibodies would prove to be an out-and-out cure.

Fortunately, there is no such epidemic, despite the grave scenarios imagined by PrP vaccine researchers (e.g. “if CWD were to cross the species barrier to humans, it would pose a major threat, likely far greater than vCJD” [Wisniewski 2012]).  In fact, to my knowledge no one has ever known themselves to have a peripheral prion infection prior to neuroinvasion, i.e. there has never been a window of intervention for treating peripheral prion disease in people.

Until, perhaps, now.  A couple of months ago MRC Prion Unit reported the discovery of a new familial prion disease mutation, Y163X [Mead 2013 (ft)], which causes decades of peripheral symptoms before neurodegeneration begins in the brain.

As a truncating mutation (the X stands for stop), this mutation has some clinical and pathological features in common with previously reported truncating mutations: Y145X [Kitamoto 1993, Ghetti 1996], Y226X, Q227X [Jansen 2010] a frameshift mutation at codon 178 [Matsuzono 2013]. In fact, Y163X was reported previously in one patient [Revesz 2009] as being simply a cerebral amyloid angiopathy (CAA) like those other truncating mutations: intense Alzheimer’s-like amyloid plaque deposition around blood vessels in the brain, with onset in middle age and death after a few years.

But now, a detailed examination of a larger family (the previously reported mutations were just a handful of individuals in total), we learn that Y163X is not only a CAA but also a more complex syndrome. These patients had chronic diarrhea beginning in their 30s – apparently due to PrPSc plaques in the intestines – and some had been misdiagnosed with Crohn’s disease. They also had peripheral neuropathy – loss of sensation in peripheral nerves – which is suggestive of a (first ever) PrP loss-of-function phenotype in a prion disease.  The most prominent phenotype of PrP knockout mice is a chronic demyelinating polyneuropathy [Bremer 2010] – peripheral axons lose their myelin over time without PrP. In mice, this phenotype wasn’t seen in het knockouts, i.e. Prnp+/- hemizygotes [Bremer 2010], so if the neuropathy observed in Y163X patients really is due to loss of PrP function, then the mechanism must be that the mutant allele abolishes the wild type allele’s function by incorporating it into plaques. Indeed, the plaques reacted with the antibody Pri-917 (against amino acids 216–221, which are absent in the mutant allele), so it appears wild-type PrP is indeed incorporated into plaques, as reported in Y145X disease [Ghetti 1996 (ft)] and some other mutations.

Eventually the Y163X patients succumbed to neurodegeneration, and it’s possible that prions had spread to the brain from the periphery, though it seems more parsimonious to assume that, probably as in other spontaneous prion diseases, the Y163X prion infection is capable of originating in the brain.  But even if treating the peripheral prion infection wouldn’t prolong the life of Y163X patients, one wonders if it could improve their quality of life for a couple of decades.  These patients could be one compelling potential use case for the PRN100 antibody.  Since it’s a very small population and since the young patients with the most to gain from treatment have also the most to lose in the event of adverse effects from a first-in-human drug, these patients may not be the most likely starting point for clinical trials. But hopefully the benefits of this antibody will reach them eventually.

Meanwhile, there’s also the question of other peripheral prion inhibitors.  For instance, the experimental compound phthalocyanine tetrasulfonate (PcTS) is highly potent against peripheral prion infection with multiple strains [Priola 2000, Priola 2003 (ft)] including mouse-passaged human strains [Abdel-Haq 2009]. As far as I know, it’s only its blood brain barrier impermeability that kept it from becoming a drug candidate. Of course, its safety profile is entirely unknown and it’s very far from being in a state where patients could have access to it.

Then there’s pentosan polysulfate (PPS), which is also a potent inhibitor of many prion strains in the periphery and/or in cell culture [Ehlers & Diringer 1984, Diringer & Ehlers 1991, Ladogana 1992, Farquhar 1999, Raymond 2006, Larramendy-Gozalo 2007].  In a previous post I lumped pentosan polysulfate in with other drug candidates as being prion strain-specific, but I no longer agree with that statement. PPS has at least some efficacy against every strain tested, and the modest differences in relative survival time in treated mice more likely just reflect differences in animal models and strains, not in PPS’s efficacy.  I’ve never heard what site on PrP it binds to, so it’s not certain it would interfere with Y163X PrP’s misfolding, but it might.  Having been reported from MRC Prion Unit, the Y163X family is presumably in the U.K., where PPS is an unapproved treatment with a fairly sour history.  Contrast this with the U.S., where pentosan polysulfate is an approved (for painful bladder syndrome) and marketed (as Elmiron) oral drug.

It’s impossible to say right now whether PPS would be helpful – especially since one reported side effect is itself diarrhea [Nickel 2005].   I’m certainly not offering medical advice or advocating the use of this drug in particular.  But more broadly, I think the emergence of a genetic prion disease with a peripheral phenotype does merit a scientific discussion of whether the progress we’ve made in treating peripheral prion disease in animal models over the past couple of decades could now be made relevant to human health, small though the target population may be.