Novel screening approaches for human prion diseases drug discovery

ABSTRACT

Introduction: Human prion diseases are rare fatal neurodegenerative diseases caused by the misfolding and aggregation of the prion protein in the form of infectious prions. So far, these diseases are incurable. One of the major difficulties in identifying suitable drugs is the availability of robust preclinical screening methods. All molecules identified have been screened using cell-based assays and in vivo murine models. The existence of a continuum of prion strains has hampered the identification of efficacious molecules modulating the progression of different forms of the disease.

Areas covered: The advent of new in vitro screening methodologies is allowing for novel strategies to develop new compounds that could interfere with a broad range of diseases. In particular, two innovative techniques named Real Time Quaking Induced Conversion (RT-QuIC) and Protein Misfolding Cyclic Amplification (PMCA) have opened new venues for testing compounds in a rapid a reproducible way. These are discussed within.

Expert opinion: For human prion diseases, one major hurdle has been a well-defined screening methodology. In other animal species, cell-based assays have been employed that could replicate animal prions indefinitely. Such a tool for human prion diseases is still missing. Therefore, the advent of RT-QuIC and PMCA has proven instrumental to overcome this limitation.

KEYWORDS:

• Human prion diseases
• RT-QuIC
• PMCA
• drug screening

Article highlights

• Human prion diseases are a group of fatal and incurable neurodegenerative disorders that are rare yet very heterogenous.

• Prions can transmit their abnormal conformations to PrP^C of the same or different species.

• The ability of PrP^Sc to replicate in the body by corrupting the conformation of PrP^C has been recently exploited for developing an in vitro assay named Protein Misfolding Cyclic Amplification (PMCA). This assay mimics the pathological process of PrP^C-PrP^Sc conversion that occurs in vivo but in a very rapid manner.

• Real-Time Quaking-Induced Conversion (RT-QuIC) is another amplification technique conceptually similar to PMCA. This technique is extraordinarily efficient.

• As already anticipated, pursuing drug discovery in prion diseases has proven an exceedingly hard task. Indeed, treatments capable of arresting or at least effectively modifying the course of all human prion diseases do not exist yet.

• Compounds emerging from the aforementioned screening assays are presently just hits, which will need to be further validated in terms of pharmacodynamic and pharmacokinetic profiles by using the existing cellular and animal models of the disease.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This manuscript was not funded.