Study Rationale:
Many people with Parkinson's disease (PD) have an abnormal glucocerebrosidase (GBA) enzyme, which causes them to accumulate fatty acids -- chemicals that make up fat -- in the brain and other organs. The exact relationship between Parkinson's and GBA abnormalities is unclear. Recent research findings suggest that replacing the abnormal, dysfunctional GBA with its functional form decreases the amount of fatty acids and blocks the buildup of alpha-synuclein, a protein that clumps in the brains of people with PD. It is, therefore, important to understand how anomalies in the GBA enzyme can affect PD symptoms.
Hypothesis:
We developed a functional GBA enzyme that reduces the buildup of fatty acids in the brains of people with a GBA mutation (a change in the GBA gene that makes this enzyme malfunction). We will investigate the effect of our enzyme on alpha-synuclein accumulation in the brain with the hope of finding that it can prevent alpha-synuclein clumping.
Study Design:
When injected in the blood stream, most therapeutic enzymes cannot reach the diseased brain cells in sufficient quantities. We will first modify our enzyme to give it this ability. Once we have several drug candidates (types of modified enzyme), we will test them in two pre-clinical models. In models with a GBA mutation, we will evaluate which candidate works best by studying the level of enzyme that reaches the brain and reduces the amount of fatty acids. In models of PD with an excess amount of alpha-synuclein in the brain, we will evaluate how much of our enzyme is needed in the brain to prevent alpha-synuclein clumping.
Impact on Diagnosis/Treatment of Parkinson's disease:
If our enzyme prevents alpha-synuclein clumping, it could be used to prevent or delay the onset of PD or to stop or slow disease progression.
Next Steps for Development:
If the enzyme prevents alpha-synuclein clumping in the model of PD, we will work to confirm our findings in another PD model. In addition, we will evaluate motor and non-motor symptoms of PD in that model. Once we have evidence that the enzyme is safe, we can move toward clinical trials.