Objective/Rationale:
The abnormal aggregation of a protein known as alpha-synuclein appears to play a critical role in Parkinson's disease. This project will explore a new type of biomolecule, known as an aptamer, as a potential inhibitor of alpha-synuclein aggregation. We aim to discover an aptamer with anti-aggregation properties and then test its ability to thwart alpha-synuclein aggregation. If these preliminary tests are promising, future work could explore how this aptamer could be used as a disease-modifying therapy.
Project Description:
Aptamers are short strands of DNA or RNA that fold up into 3D shapes that are capable of binding to a target molecule with remarkable specificity and affinity. Our goal is to find a DNA aptamer that can bind tightly to alpha-synuclein and prevent it from aggregating. We will first test aptamers for their ability to block alpha-synuclein aggregation in cellular experiments. Next, we will package our best aptamer candidates in lipid nanoparticles to deliver them into the brains of pre-clinical models that exhibit Parkinson’s-like symptoms in order to test the aptamer efficacy.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Identification of an aptamer that can bind to alpha-synuclein in the brain and stop it from forming toxic aggregates could be an important advance. As a research tool, the aptamer could be used to better understand how alpha-synuclein aggregation is implicated in Parkinson’s disease. As a therapeutic, an aptamer with the ability to block alpha-synuclein aggregation could potentially slow or halt disease progression.
Anticipated Outcome:
This project represents an important first step that will explore the feasibility of developing DNA-based aptamer therapeutics as an alternative treatment strategy for Parkinson’s disease. By the end of this two-year pilot project, there will be a clear “go/no go” decision for moving an aptamer-based therapeutic strategy toward ultimate clinical utility in people with Parkinson’s disease.
Final Outcome
Aptamers are short strands of the cell's genetic material, DNA, folded in 3D shapes that can bind to other molecules, e.g., alpha-synuclein, a sticky protein that clumps in the brains of people with Parkinson's disease (PD). This study aimed to find an aptamer that can bind tightly to alpha-synuclein and prevent it from clumping. We developed a novel strategy to discover aptamers and used it to identify five aptamer candidates. Using a very powerful microscope, we evaluated the size and shape of alpha-synuclein after it had been treated with the aptamer. All of the aptamer candidates reduced the size of alpha-synuclein clumps. Further, the best aptamer, a-syn-1, prevented the formation of alpha-synuclein clumps in vitro. This aptamer was combined with other molecules to help it travel to the brain of pre-clinical models of Parkinson's that produce human alpha-synuclein. Using a-syn-1 bound to alpha-synuclein as a tag, we also evaluated the distribution of alpha-synuclein in the brain.
April 2017