Repurposing approved human drugs to treat prion diseases

Prions are abnormal pathogenic agents that can be transmitted and cause certain normal cellular proteins to misfold. Prion diseases is the general name for a group of incurable and fatal neurodegenerative diseases that affect not only humans, but also wild and domestic animals. These diseases include Creutzfeldt-Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE, or “mad cow disease”), and chronic wasting disease (CWD), which affects deer, elk and elk.

The main event in these diseases is the conversion of the prion protein (PrPC) from its normal form to a pathological structure (PrPSc), which is toxic to neurons and can self-replicate by binding to unconverted PrPC molecules. This ability to self-replicate makes these misfolded proteins infectious, which has enormous public health implications.

In a new study, researchers from the Chobanian and Avdisian School of Medicine at Boston University identified 10 compounds that were able to reduce PrPSc levels in infected cells and showed that the most potent molecules could also prevent the toxicity observed when PrPSc was applied to cultured neurons.

"Excitingly, five of these molecules are already in medical use: rimcazole and haloperidol for the treatment of neuropsychiatric conditions, (+)-pentazocine for the treatment of neuropathic pain, and SA 4503 and ANAVEX2-73 are in clinical trials for the treatment of ischemic stroke and disease Alzheimer's, respectively," explained lead author Robert S.S. Mercer, Ph.D., teaches biochemistry and cell biology at the school.

Researchers initially studied the antiprion properties of these molecules because they were known to bind to sigma receptors (σ1R and σ2R), which were thought to be involved in prion proliferation. Using gene knockout technology (CRISPR), they found that sigma receptors are not the targets of these drugs in terms of their antiprion properties.

Using Neuro2a (N2a) cells from a prion-infected experimental model, these cells were exposed to increasing concentrations of each drug and PrPSc levels were determined. They then used CRISPR technology to "edit" the σ1R and σ2R genes so that they no longer coded for the protein, and found that this had no effect on the reduction in PrPSc levels seen with the drugs. This led them to conclude that σ1R and σ2R are not responsible for the antiprion effects of these drugs. They then tested the ability of these drugs to inhibit the conversion of PrPC to PrPSc and found that they did not affect these reactions outside cells, indicating that another protein was involved in the actions of these drugs.

Prion diseases have enormous public health implications, from the safety of the blood supply to the proper disinfection of surgical instruments used in neurosurgery, researchers say. "From a clinical perspective, we believe this study has identified antiprion properties of drugs that have already been shown to be safe for use in humans. Because of this, especially given the lack of effective treatments for these diseases, these compounds could be repurposed for the treatment of prion diseases," said The study's senior author, David A. Harris, MD, PhD, is a professor and chair of the school's Department of Biochemistry and Cell Biology.

These results are published online in the journal ACS Chemical Neuroscience.