Funded Studies
Objective/Rationale:
Mutations in the GBA1 gene increase the risk of Parkinson’s. These mutations reduce the activity of the enzyme glucocerebrosidase (GCase), which is deficient in the lysosomal storage disorder known as Gaucher disease. Pharmacological Chaperones (PC) are orally-available small molecules that provide a new way of increasing enzyme activity. AT3375 is a PC that increases GCase enzyme activity in tissues including the brain. Compared to first-generation PCs, AT3375 has improved access to the brain, greater ability to increase GCase, and rapid exit from the brain, all of which are important for the use of PCs to treat Parkinson’s.
Project Description:
Accumulation of alpha-synuclein in the nervous system is a hallmark of Parkinson’s. This study focuses on the reduction of alpha-synuclein and synuclein-dependent changes in the brain such as loss of the neurotransmitter dopamine. AT3375 will be administered to a pre-clinical model genetically engineered to produce an excess of alpha-synuclein (ASO). The effect of AT3375 will be assessed by measuring behaviors that are sensitive to brain alpha-synuclein levels and determination of the amount of brain alpha-synuclein. A second group will be aged to 10 months at which time they begin to lose dopamine. This group will receive the optimal dose of AT3375 to determine if dopamine loss and alpha-synuclein accumulation is reduced.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
GBA1 mutations are a risk factor for Parkinson’s, even when only one copy of the mutant gene is inherited. Mutations in GBA1 reduce the ability of GCase to carry out its normal function. Increasing the activity of GCase with AT3375 may reduce the negative consequences of inherited GBA1 mutations. These experiments will determine the likelihood that AT3375 will slow the progression or delay the onset of Parkinson’s disease in humans.
Anticipated Outcome:
With AT3375, we improved the ability of the PC to enter the brain and reduced the dose necessary to increase GCase activity. Administration of a first-generation PC to an ASO pre-clinical model led to decreased synuclein and improvements in motor deficits sensitive to excess synuclein. If the improved properties of AT3375 translate in this study to more robust effects in the pre-clinical model, this will pave the way to studies with AT3375 in humans.
Final Outcome
The effect of elevating brain GCase (a lysosomal enzyme) activity with a compound (AT3375) given orally was investigated by the Chesselet laboratory at UCLA in a pre-clinical model of Parkinson’s that produces excess alpha-synuclein, a protein implicated in Parkinson’s disease. In young pre-clinical models, one of the AT3375 dose levels decreased brain inflammation, improved motor function, and lessened the accumulation of alpha-synuclein in a nerve cell type affected by Parkinson’s disease, the nigral dopaminergic neurons. In aged pre-clinical models of the same type, the anticipated loss of dopamine was not realized, presumably due to a protective effect of repeated handling, and this precluded the assessment of AT3375 effects on dopamine levels. Nonetheless, AT3375 prevented the development of reduced motor activity in these mice, indicating beneficial effects in both young and older mice, without evidence of toxicity at either age. In both studies, AT3375 had the desired effect of increasing the amount of GCase in the brain; however, measurements of the lipids that are normally degraded by GCase suggest that the increased GCase was not fully active. Considering the potency of AT3375, lower doses or less frequent administration may be better suited to unlock its full potential.
PARTNERING PROGRAM
This grant was selected by The Michael J. Fox Foundation staff to be highlighted via the Foundation’s Partnering Program.