Background Prion diseases such as Creutzfeldt-Jakob disease (CJD) are invariably fatal neurodegenerative diseases that are caused by the autocatalytic formation of a misfolded protein, PrPSc. The biosynthesis and degradation of PrPSc in neuronal cells involves many specific steps, and various classes of therapeutic drugs are available to modulate nearly all of those steps. Unfortunately, no single drug appears to be able to slow the progression of prion disease when administered alone (monotherapy) after the onset of clinical symptoms (which is the relevant clinical scenario when patients are initially diagnosed). Moreover, drug-resistant prions can emerge from a collection of pre- existing PrPSc quasi-species during monotherapy with PrPSc replication inhibitors. Historically, combination chemotherapy has been used successfully to cure a variety of diseases, including many types of infectious diseases and cancer, in which monotherapy failed. In addition, the use of combination regimens typically suppresses drug-resistance in these scenarios by exerting overwhelming selective pressure on replicating pathogens or tumor cells. Proposed Experiments We will compare combination chemotherapy against monotherapy in treating scrapie-infected mice after the onset of clinical symptoms, using a variety of anti-prion compounds previously shown to have efficacy as prophylactic agents. We will specifically study two types of combination regimens: a mixture of different PrPSc replication inhibitors (mAbs directed against different PrP epitopes) (Aim 1), and a mixture of small molecule compounds that target different steps of PrPSc biosynthesis (Aim 2). For each experimental group, we will measure overall survival, and simultaneously perform longitudinal assays of prion titer, drug resistance, and replication kinetics during treatment. If any experimental treatment is able to eliminate prion infectivity (as judged by the longitudinal assays of prion titer), we will also test for the possibility of durable cure by discontinuing therapy. In summary, we propose to perform the first trial of combination chemotherapy to cure symptomatic prion disease using a bona fide animal model of symptomatic prion disease. Our rigorous experimental design will provide clear quantitative data that can be used to critically evaluate the potential utility of this strategy in an authentic clinical setting, and also begin to identify the essential components of an optimal therapeutic regimen.

Public Health Relevance

Prion diseases such as Creutzfeldt-Jakob disease (CJD) are invariably fatal brain diseases caused by the replication of a specific misfolded protein for which there is currently no effective treatment. Over the past 20 years, basic scientists have discovered a variety of anti-prion compounds that have different mechanisms of action. Thus far, none of these compounds have been effective in slowing disease progression when given alone (monotherapy) after the onset of clinical symptoms. Furthermore, monotherapy has also resulted in the emergence of drug-resistant prions. Historically, combination chemotherapy has proven to be a superior alternative to monotherapy in treating many other diseases, including bacterial infections, viral infections, and cancer. In this proposal, we will rigorously evaluate combination chemotherapy as a strategy to treat symptomatic prion disease using a bona fide animal model of symptomatic prion disease. In addition, we will evaluate the effectiveness of specific types of drug combinations in preventing the emergence of drug resistance, slowing prion replication, and curing clinical disease. Our study represents the first attempt to evaluate a therapeutic strategy for prion disease that historically has been effective for many other types of diseases. Because misfolded proteins cause other ?prion-like? brain diseases such as Alzheimer's and Parkinson's disease, the results of ours studies may eventually lead to a new treatment approach for a very broad group of patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS099928-02
Application #
9442871
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Wong, May
Project Start
2017-03-01
Project End
2019-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
2
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Dartmouth College
Department
Biochemistry
Type
Schools of Medicine
DUNS #
041027822
City
Hanover
State
NH
Country
United States
Zip Code
Supattapone, S Y; Supattapone, S; Cramer, R A (2017) The effect of reducing agents on challenge of rainbow trout with AeromonasĀ salmonicida. J Fish Dis 40:437-441