Abstract
Prions are unorthodox infectious agents that replicate by templating misfolded conformations of a host-encoded glycoprotein, collectively termed PrPSc. Prion diseases are invariably fatal and currently incurable, but oral drugs that can prolong incubation times in prion-infected mice have been developed. Here, we tested the efficacy of combination therapy with two such drugs, IND24 and Anle138b, in scrapie-infected mice. The results indicate that combination therapy was no more effective than either IND24 or Anle138b monotherapy in prolonging scrapie incubation times. Moreover, combination therapy induced the formation of a new prion strain that is specifically resistant to the combination regimen but susceptible to Anle138b. To our knowledge, this is the first report of a pathogen with specific resistance to combination therapy despite being susceptible to monotherapy. Our findings also suggest that combination therapy may be a less effective strategy for treating prions than conventional pathogens.
Highlights
Prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans, Chronic Wasting Disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE) in cattle, are a group of invariably fatal neurodegenerative diseases that are caused by unorthodox infectious agents that contain misfolded conformers of a host glycoprotein (PrPC)
Combining two or more drugs has proven to be an effective strategy for treating other infectious agents and cancer cells, and here we evaluated the effectiveness of treating experimental prion disease with a combination of two oral drugs previously shown to prolong the lives of prion-infected mice
Our results show that the combination regimen was no more effective than either of the individual drugs
Summary
Prion diseases, such as Creutzfeldt-Jakob disease (CJD) in humans, Chronic Wasting Disease (CWD) in cervids, and bovine spongiform encephalopathy (BSE) in cattle, are a group of invariably fatal neurodegenerative diseases that are caused by unorthodox infectious agents that contain misfolded conformers (collectively termed PrPSc) of a host glycoprotein (PrPC). There are three major barriers to treating prion disease in clinical settings. All anti-prion therapies are essentially ineffective at this late stage due to the large burden of accumulated PrPSc[3]. When prion-infected animals are treated with compounds that target PrPSc replication, drug-resistant PrPSc quasispecies emerge, resulting in treatment failure[8, 9]. These two problems (large PrPSc burden and the emergence of drug-resistant PrPSc quasi-species) are closely related, since having a high rate of PrPSc formation increases the probability of generating a drug-resistant PrPSc conformer. Some drugs that are effective at treating one prion strain may be ineffective at treating or even facilitate the propagation of a different strain[10, 11]
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