# Novel therapeutic strategies targeting malleability of wild-type and mutant prions

> **NIH NIH R01** · DARTMOUTH COLLEGE · 2021 · $530,216

## Abstract

Prion diseases are invariably fatal neurodegenerative disorders that occur in sporadic,
infectious, and inherited forms, and are caused by the conversion of either wild-type or mutant
versions of the cellular prion protein (PrPC) into self-propagating, misfolded conformers
(collectively termed PrPSc). There is currently no clinically effective treatment for any form of
prion disease.
Recently, chemical screens have identified different classes of oral drugs that can significantly
decrease the rate of wild-type PrPSc formation, and thereby increase disease-free survival in
prion-infected animals. However, in each case, drug treatment did not cure prion infection,
which eventually overwhelmed the treated animals. In almost all cases, an alternative PrPSc
conformation emerged during therapy, causing prion strain adaptation and, in some cases, drug
resistance. Interestingly, prions from drug-treated animals can recover their original strain
characteristics and drug susceptibility during serial passage in untreated hosts. In addition, our
preliminary work shows that simultaneous co-administration of two different drugs to prion-infected mice failed to create a synergistic effect due to the emergence of an unorthodox new
strain that is resistant to the two-drug combination yet susceptible to both drugs alone. Taken
together, these observations show that wild-type prions are highly malleable, i.e. able to
switch back and forth between different PrPSc conformations in response to changes in selective
pressure caused by anti-prion drug therapy. The molecular mechanism responsible for the
malleability of wild-type prions is currently unknown. It is also unknown whether mutant prions,
which specifically cause the inherited forms of prion disease, are as malleable as wild-type
prions. The overall objectives of this proposal are to evaluate novel therapeutic strategies that
rationally target prion malleability, and to study the role of cofactor molecules in drug-induced
prion strain adaptation. Specifically, we will: (1) evaluate the efficacy of alternating oral drug
regimens in a wild-type prion infection model; (2) determine whether cofactor selection plays a
role in the mechanism by which wild-type prions acquire drug resistance; and (3) test the
efficacy of oral drug regimens in new knock-in mouse models of inherited prion diseases.

## Key facts

- **NIH application ID:** 10191066
- **Project number:** 5R01NS117276-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Surachai Supattapone
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $530,216
- **Award type:** 5
- **Project period:** 2020-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10191066

## Citation

> US National Institutes of Health, RePORTER application 10191066, Novel therapeutic strategies targeting malleability of wild-type and mutant prions (5R01NS117276-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10191066. Licensed CC0.

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