Results tagged “prion diseases” from Pathophilia
Probably.
Laura Manuelidis and her colleagues at Yale continue to chip away at the idea that prions—proteinaceous infectious particles—cause transmissible spongiform encephalopathies (TSEs) all by themselves. (For background on this story, start here.) Her group's latest work to undermine the prion hypothesis, for which Stanley Prusiner received the Nobel Prize in 1997, was somewhat stealthily published in the August 11th issue of PNAS.
According to the prion hypothesis of disease, the normal, endogenous form of prion protein (PrP) misfolds to become infectious. (This abnormal, disease-associated form of PrP, which is resistant to degradation, is denoted PrP-res.) PrP misfolding may occur spontaneously, through genetically encoded triggers, or by the inoculation or ingestion of misfolded PrP from infected tissues. The last method is apparently how kuru, sheep scrapie, and variant Cretuzfeld-Jacob disease (or vCJD, from bovine spongiform encephalopathy [BSE]) are propagated.
The prion hypothesis also stipulates that conversion of normal PrP into PrP-res is only possible when there is considerable homology between the donor and host PrP. But, as Manuelidis points out, this idea has not been consistently supported by animal experiments. For instance, the vCJD agent has been readily transmitted to normal mice but not to transgenic mice that expressed only human PrP. Data also show that PrP-res Western-blot profiles do not vary with different infectious TSE agents, as would otherwise be expected.
Other problems with the prion hypothesis include the inability to demonstrate the reliable infectivity of purified PrP-res and the fact that tissue samples without PrP-res can transmit infection. Arguably the most heretical aspect of the prion hypothesis is that the infectious agent, unlike bacteria or viruses, does not contain nucleic acid—that is, DNA or RNA.
For these reasons, it remains difficult for many to wholeheartedly embrace the prion hypothesis, despite its now wide acceptance within the scientific community.
Contradicting the proposal that donor and host PrP must be homologous to transmit TSE, Manuelidis et al showed in PNAS that high levels of murine wild-type PrP did not prevent the transmission of primate kuru to mice. Instead high levels of murine wild-type PrP shortened the incubation time of disease—a phenomenon that would be expected if PrP acts as a viral receptor, she argued. Mouse experiments with the infectious agents for sporadic CJD, BSE, and scrapie also showed incubation times, pathologic features in the brain and spleen, and animal behaviors that were distinct from those of kuru.
Ultimately Manuelidis proposes that host PrP is required for TSE infection, but that it probably acts as a receptor or "scaffold" for the true infectious agent—which is possibly a 25-nm virus-like particle, at least in the case of scrapie.
The primary manner in which bovine spongiform encephalopathy (BSE, or mad cow disease) is transmitted is through the ingestion of feed that contains contaminated tissue—eg, meat, bone meal, or nervous tissue from an infected animal. Therefore, to reduce the spread of BSE, the Canadian government banned certain potentially infectious animal tissues, or specified risk material* (SRM), from cattle feed in 1997.
However, cases of BSE in Canada began occurring in cows born after the 1997 feed ban. As a result, the government instituted a wider feed ban last year, in which SRM were to be eliminated from all other animal feeds, pet foods, and fertilizers. This new measure is intended to reduce the risk of any cross-contamination of cattle feed with the BSE-causing agent, and the Canadian Food Inspection Agency estimates that BSE will be eliminated from Canadian cattle by 2017.**
Like Canada, the United States instituted an FDA-mandated feed ban in 1997, which applied only to cattle feed. But as part of the USDA's BSE surveillance system, 2 cases of BSE in American-born cattle were discovered in 2005 and 2006, respectively. In both cases, the affected cows were born before 1997. Nevertheless, to enhance BSE prevention, the FDA is instituting a more rigorous feed ban in April of next year, consistent with the latest feed ban of the Canadian government.
The FDA's enhanced feed ban eliminates the following from the food or feed of all animals:
- the entire carcass of a BSE-positive cow;
- the brain and spinal cord of a cow aged 30 months or older;
- the entire carcass of a cow not inspected and passed for human consumption that is 30 months of age or older from which the brain and spinal cord have not been removed;
- the tallow (ie, rendered beef fat) from a BSE-positive cow;
- the tallow derived from other prohibited materials that contain >0.15% insoluble impurities; and
- mechanically separated beef that is derived from prohibited materials.
A recent AP article suggests that next year's FDA feed ban will pose health risks of its own, because of the new burden of carcass disposal placed on ranchers or dairy farmers. Rendering plants may no longer accept dead cattle owing to the costs of removing SRM before feed production, or these plants may charge higher prices for processing dead cows. Consequently ranchers and farmers may be more likely to dispose of certain dead cattle by burying, composting, or leaving the carcasses out in the open for scavengers. (These measures are already used to avoid rendering-plant fees.) Unfortunately there is no indication in the AP article how Canadian cattle producers have adjusted to their enhanced feed ban during the last year.
* For example, cow brains, eyes, and spinal cords. According to the FDA, ~90% of BSE infectivity is contained in the brain and spinal cord, and ~10% is present in the retina, ganglia, and distal ileum.
** Presumably at a time when cattle born before the 2007 feed ban are no longer with us.
Photo of BSE-affected cow from Wikipedia.
Yesterday, the Canadian Food Inspection Agency confirmed another case of the prion-generated disease, bovine spongiform encephalopathy (aka mad cow disease) since national surveillance began in 1992. The affected animal was a 7-year-old dairy cow from British Columbia, and investigators are currently tracing the animal's origin and herdmates. However, the agency assures the public in its standard mantra, "No part of the animal's carcass entered the human food or animal feed systems."
The latest case of BSE is the fourth identified so far this year in Canada. The CDC provides a graphic tally of BSE cases detected to date in North America, excluding the latest case.
A more stringent feed ban was instituted in Canada last year, and the Canadian agency expects that BSE should be eliminated from Canadian cattle by 2017. In April of next year, an FDA-regulated enhanced feed ban in the United States will go into effect.
UK researchers indicate that minimal progress has been made in treatment of prion diseases, such as sporadic Creutzfeld-Jakob disease (sCJD) or the human variant of bovine spongiform encephalopathy (vCJD), during the last 30 years. Their literature review, published in the April 8 issue of Neurology, identified only 1 randomized, placebo-controlled trial of therapy since 1971. The investigators describe many of the examined studies as "flawed" or "poorly reported."
In total, the authors found 33 studies (including case reports) that evaluated a total of 14 interventions (N = 149); 10 of the reports included fewer than 4 patients. Most of the studies evaluated patients with sporadic or unspecified CJD. Examined therapies included analgesic, anticoagulant, anticonvulsant, antidepressant, and antimicrobial drugs.
Therapies studied in the greatest (relative) detail:
Amantadine: The authors identified 2 "questionable" comparative studies (n = 17) and 6 case reports (n = 7), most of which were published during the 1970s. Transient, symptomatic benefits were described for some patients in 1 of the comparative studies and in 3 of the case reports.
Pentosan polysulfate: Disease progression may have been slowed by the anticoagulant in some patients, according to 3 published cases of vCJD and cursory descriptions of another 23 patients.
Quinacrine: In 1 comparative study (N = 32), there were no obvious differences in clinical status or survival between treated patients and "matched concurrent controls." Case studies (N = 50) inconsistently reported symptomatic benefit, and drug-related toxicity (ie, liver dysfunction) was described in 10 studies.
Flupirtine: In the "only reliable reported randomized trial," the analgesic may have slowed cognitive decline, as measured by the cognitive portion of the ADAS-cog. Enrolled patients either had sCJD (n = 26) or genetically determined CJD (n = 2).
Given the rarity of prion diseases (quoted incidence of sCJD = 1 in a million), adequately powered trials will require national and, probably more likely, international collaboration, as the authors indicate. Also logical choices for tested therapies will necessitate a better understanding of how prion diseases are initiated and a more universal consensus of their cause (for an examination of the contentious, opposing views on the prion theory, click here).
