16 August 2002 10:20 EST

by Josh P. Roberts, BioMedNet News

To date there is no effective way to prevent or treat most prion diseases such as Creutzfeldt-Jakob disease (CJD). Now researchers have shown that it is possible to delay the onset of a prion-based disease in mice, using a recombinant protein to immunize them. This won't lead to a way to vaccinate humans against CJD any time soon. But if perfected, it could help protect herds of livestock or game living in the wild.

Biochemist Stanley Prusiner, who won the Nobel Prize for his pioneering research on prions, has speculated that "virtually all neurodegenerative disorders involve abnormal processing of neuronal proteins." If this is true, then insights from recent attempts to treat diseases such as Alzheimer's - which affects more than 4 million people in the United States alone - may have a profound bearing on research into other maladies such as prion diseases.

Work in transgenic mouse models of Alzheimer's has shown that immunizing them with variants of the implicated protein can ameliorate various manifestations of the disease. Transfer of antibodies against these proteins, too, has the capacity to prevent or clear amyloid plaques.

But to date the other prion diseases - which include CJD, scrapie in sheep, bovine spongiform encephalopathy (BSE) in cattle, and chronic wasting disease in deer - have been uniformly untreatable and fatal. Based on the earlier mouse work on Alzheimer's, a New York team wagered that a similar approach might prove effective in similar neuropathies. Now, in a study published in the American Journal of Pathology, neurologist Thomas Wisniewski of New York University (NYU) and his collaborators provide the first report to show any promise of an immunological approach to treating prion diseases. Other approaches thus far have all been limited by toxicity or pharmacokinetic concerns.

Like other neurodegenerative pathologies, prion diseases are associated with the accumulation of aberrant proteins in the central nervous system. The plaques blamed for the damage in these diseases are composed of a protein known as PrP^Sc ("Sc" for "scrapie"), which is believed to "reproduce" by recruiting normal cellular proteins (known as PrP^C) and somehow inducing them to convert to the pathogenic form.

PrP^Sc is identical in sequence to PrP^C, but it differs in three-dimensional conformation. These aberrant proteins do not elicit a classical immune response, presumably because they are not seen as foreign. But Wisniewski and colleagues have overcome this obstacle by vaccinating mice with recombinant PrP (recPrP) mixed with a powerful adjuvant: heat-killed mycobacteria. Mice thus immunized develop the model prion disease later after inoculation with PrP^Sc, compared to unvaccinated controls. There is a significant correlation between a delay in the onset of disease and a high antibody titer to PrP^Sc, especially at higher inoculation doses.

Wisniewski is extremely circumspect about the potential of the immunization approach for the direct prevention of prion diseases in humans. "Down the road, with further development, it might be used as a vaccine, potentially, for human populations [such as] health care workers who are at risk of exposure."

"We need to be very cautious about toxicity," he added. Immunizing against Alzheimer's disease has caused encephalitis and meningitis, Wisniewski observed, which should give researchers pause about using similar methods to prevent prion diseases, which are similar to Alzheimer's.

However, the work could bear relevance to humans even if it never reaches them directly. Wisniewski says it is reasonable to expect that animal trials could begin in three or four years - perhaps on deer which, in the western US, have upwards of 40% incidence of chronic wasting disease. There is growing concern that hunters may develop prion-based diseases if they eat meat from deer with the disease.

Even as a preventive strategy in animals, these results fail to impress another researcher who has studied scrapie and Alzheimer's disease. The immunization "clearly isn't very protective," comments microbiologist Steven Wietgrefe of the University of Minnesota. Vaccination, he points out, delayed the onset of disease - which has a normal incubation period of perhaps 175 days - by only about 10 days. "For protecting deer and elk herds," he says, "it probably wouldn't be worth the trouble if the vaccine delays, but does not stop, the infection."

The New York researchers are working toward outright protection. The key, Wisniewski hypothesizes, is higher antibody titers. To this end, they are looking for better adjuvants, using mutated variants of the recPrP vaccine. They hope these variants will elicit a stronger immune response while being less likely themselves to take on the beta-pleated sheet conformation characteristic of pathogenic prion proteins.

The group is also trying a variety of multi-faceted approaches, such as passively immunizing some test animals with anti- PrP^Sc antibody preparations. And to boost the IgA antibody response, they have begun feeding mice with recPrP. (Subcutaneous immunization induces principally IgG2a and IgG2b.) Since scrapie infections often arise in nature via the gut, Wisniewski reasoned, "we might be able to hinder penetration of the agent into the body."

Wietgrefe also voiced concern over the lack of any discernable histopathological difference between the brains of vaccinated versus control animals. This may be due to the assays being conducted only on mice that had reached their clinical endpoint, regardless of how long it took them to get there.

Because the clinical incubation period is about 175 days, scientists in this field currently must wait nearly half a year before they can know whether any treatment (or set of treatments) has had any effect. The NYU researchers are gearing up to address this issue by using MRI to assess damage to the brains of inoculated mice, which may appear long before any neurological symptoms become apparent. An added benefit is that this approach requires far fewer mice than histological examinations, because it does not require destroying the animals. Thus it is easier to test several treatments concurrently.

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See also:
Is an effective immune intervention for Alzheimer's disease in prospect?
[Research News]
Margaret M. Esiri
Trends in Pharmacological Sciences, 2001, 22:1:2-3

Immunization delays the onset of prion disease in mice
Sigurdsson EM, Brown DR, Daniels M, et al.
Am J Pathol, 2002 Jul 161:13-7
 

Related links on other sites:
Shattuck Lecture - Neurodegenerative diseases and prions
Prusiner, S.
N Engl J Med, 2001 - 344, 1516-26
 

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