Compositions and methods of use thereof for treatment of proteinopathies
The present disclosure relates generally compositions and methods of using the same for the treatment of proteinopathies (e.g. Alpha-1-antitrypsin deficiency, Non-alcoholic fatty liver disease, Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis, and Huntington's disease) with one or more proteotoxicity reducing agents.
1. A method for treating a subject having or suspected of having alpha-1-antitrypsin deficiency (ATD), wherein the subject has not developed hepatocellular carcinoma, the method comprising: administering to the subject a therapeutically effective amount of a composition comprising one or more of a proteotoxicity reducing agent selected from Tricyclic antipsychotics, Vasodilators, Antibiotics/Antiseptics, and Aryl piperazines.
2. The method of claim 1 , wherein the composition comprises a Prochlorperazine and a second proteotoxicity reducing agent selected from Amlodipine, Nilvadipine, Alexidine, Chlorhexidine, Hexetidine, Auranofin, Sertraline, Toremifene, Perhexiline, Aprepitant, and Desloratadine.
3. The method of claim 1 , wherein the composition comprises Amlodipine and a second proteotoxicity reducing agent selected from Amlodipine, Nilvadipine, Alexidine, Chlorhexidine, Hexetidine, Auranofin, Sertraline, Toremifene, Perhexiline, Aprepitant, and Desloratadine.
4. The method of claim 3 , wherein the second proteotoxicity reducing agent is selected from Perhexiline and Desloratadine.
5. The method of claim 1 , wherein alpha-1-antitrypsin Z misfolding or accumulation is reduced relative to an untreated subject.
6. The method of claim 1 , wherein clearance of a misfolded or mutant protein alpha-1-antitrypsin Z from the liver is enhanced.
7. The method of claim 1 , wherein autophagy in a hepatocyte having a misfolded or mutant alpha-1-antitrypsin Z is enhanced.