Investigation on the potential of alpha-synuclein knockdown peptides as a novel therapy for Parkinson’s disease
University of British Columbia
Parkinson’s disease (PD) is one of the major brain disorders that affects over 1.5 million people in North America. There is a significant loss of cells in the brain of patients with PD that causes severe motor disorders such as tremor, rigidity, bradykinesia and impaired balance, and non-motor disorders such as cognitive impairment and sleep dysfunction. To date, there is no effective treatment that directly targets the causes of the disease. Current clinical approaches, like deep brain stimulation and pharmacological treatments, are only symptom-relieving and their efficacy is also greatly limited by their undesirable complications and side effects. Accumulating evidence supports that brain cell loss in PD is at least in part caused by aggregation of a protein called α-synuclein in the cells. We hypothesize that reducing the level of α-synuclein in the diseased brain would represent an effective therapeutic that specifically targets the cause of the disease, and thereby stopping the disease progression and reduce symptoms of PD patients. In this proposed study, we will use an innovative protein knockdown technology recently developed in our laboratory to develop clinically-applicable peptide drugs that can effectively and specifically reduce the level of α-synuclein in the brain by targeting it for degradation, and test their therapeutic potentials in reducing PD-related pathologies and symptoms in well-established pre-clinical models of PD.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
By efficiently removing α-synuclein from the brain of PD patients, our clinically-applicable peptide drugs may represent the first class of PD therapy that stop or slow down the progression of the disease by directly targeting the disease-causing process. Furthermore, the innovative and versatile protein knockdown technology we have recently developed in the laboratory theoretically allows us to target any disease-causing protein in the cell. Since many neurodegenerative diseases of aging such as Parkinson’s disease and Alzheimer’s disease are caused by up-regulation and/or mutation of a particular disease protein, our cutting-edge technology can be expected to spur the development of novel therapeutics for human diseases beyond PD.
If all the experiments proposed here work well, we predict to see that daily administration of our peptide drugs efficiently reduces the level of PD-causing protein (α-synuclein) in the brain, and thereby robustly reduce PD pathologies and symptoms in preclinical models of PD. Therefore, these clinically-applicable peptide drugs may represent innovative therapeutic treatments for PD with great potential to be quickly translated to the clinic.
Over the course of this project, we have obtained many exciting results. We have successfully synthesized peptides aimed at lowering the levels of the α-synuclein protein. We found that intranasal administration of α-synuclein knockdown peptides led to a robust reduction in the endogenous α-synuclein levels in several brain regions of wild-type mice in a dose-dependent and time-dependent manner. Additionally we found that a single intraperitoneal administration of α-synuclein knockdown peptides induced a robust reduction in the endogenous α-synuclein levels in the kidney, the spleen, the striatum and the ventral midbrain of wild type mice in a time-dependent manner.