Prion therapeutics: Lessons from the past

Abstract

Prion diseases are a group of incurable zoonotic neurodegenerative diseases (NDDs) in humans and other animals caused by the prion proteins. The abnormal folding and aggregation of the soluble cellular prion proteins (PrP C ) into scrapie isoform (PrP Sc ) in the Central nervous system (CNS) resulted in brain damage and other neurological symptoms. Different therapeutic approaches, including stalling PrP C to PrP Sc conversion, increasing PrP Sc removal, and PrP C stabilization, for which a spectrum of compounds, ranging from organic compounds to antibodies, have been explored. Additionally, a non-PrP targeted drug strategy using serpin inhibitors has been discussed. Despite numerous scaffolds being screened for anti-prion activity in vitro , only a few were effective in vivo and unfortunately, almost none of them proved effective in the clinical studies, most likely due to toxicity and lack of permeability. Recently, encouraging results from a prion-protein monoclonal antibody, PRN100, were presented in the first human trial on CJD patients, which gives a hope for better future for the discovery of other new molecules to treat prion diseases. In this comprehensive review, we have re-visited the history and discussed various classes of anti-prion agents, their structure, mode of action, and toxicity. Understanding pathogenesis would be vital for developing future treatments for prion diseases. Based on the outcomes of existing therapies, new anti-prion agents could be identified/synthesized/designed with reduced toxicity and increased bioavailability, which could probably be effective in treating prion diseases.

Radotinib Decreases Prion Propagation and Prolongs Survival Times in Models of Prion Disease

“…In these models, radotinib reduced PrP Sc propagation, which may have resulted in prolonged survival times of prion-affected hamster models. To date, it has been a challenge to find or develop effective anti-prion drugs as well as drugs for the treatment of other neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease [23][24][25][26]. In particular, the duration of illness is typically shortened by approximately 18 months after signs and symptoms appear.…”

Possible Treatments for COVID Vaccine Induced Prion Disease

“…The agent would need to cross the blood brain barrier to work in brain. A number of review papers were utilized to help identify potential antidotes to COVID "vaccine" induced prion disease [19][20][21][22][23].…”

Potential Therapeutic Use of Stem Cells for Prion Diseases

“…Because the conversion of PrP C to PrP Sc is essential for prion pathogenesis, drugs that target this pathway are attractive treatment prospects for prion diseases [42]. Many elements of prion conversion might be studied, for example, compounds such as polysulfated polyanionic, polyamine, tetrapyrroles, polyene antibiotics, tetracyclic, tricyclic, and peptides [43]. Nevertheless, these drugs have minimal therapeutic impact on disease progression in vivo, poor bioavailability, and need further clinical trials [43].…”

“…Many elements of prion conversion might be studied, for example, compounds such as polysulfated polyanionic, polyamine, tetrapyrroles, polyene antibiotics, tetracyclic, tricyclic, and peptides [43]. Nevertheless, these drugs have minimal therapeutic impact on disease progression in vivo, poor bioavailability, and need further clinical trials [43]. Moreover, they have only been demonstrated to slow disease development when given prophylactically around the time of prion inoculation and when the infection is limited to the lymphoreticular system [44].…”