Molecular and Technological Advances in the Treatment of Protein Misfolding Disorders

Protein misfolding and aggregation are fundamental pathophysiological events in several major human diseases, especially Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and systemic amyloidosis. Such accumulation of misfolded protein polymers, especially amyloid fibrils and inclusion bodies, disrupts normal cellular functions, eventually leading to cell death and tissue destruction. As such, therapeutic approaches to protein aggregation have gained much attention in biomedical studies. This discussion is a review of recent molecular and technological approaches to the treatment of protein misfolding disorders, focusing on both therapeutic developments and translation issues. Examples include protein misfolding inhibitors, preformed aggregate disaggregants, and cellular clearance mechanism enhancers. Pharmacological chaperones are a new category of drugs developed to maintain the native form of proteins and inhibit early aggregation. Also, a number of small molecules in preclinical and clinical stages display promise in disrupting amyloid fibril formation through β-sheet interactions. The future of immunotherapy, specifically monoclonal antibodies that can recognize and destroy protein aggregates, is also addressed. Moreover, gene therapy and RNA interference technologies have been successful in inhibiting the expression of aggregation-prone proteins. The roles of autophagy and the ubiquitin-proteasome system in the removal of misfolded proteins and ways to optimize these two systems are described. The improving specificity and efficacy of anti-aggregation therapies with the aid of nanotechnology and nanoscale drug delivery systems have further potential due to current advances in nanotechnology and nanoscale drug delivery systems. Such combined strategies can present additional opportunities for individually tailored therapy in neurodegenerative disorders.