Funded Studies
Objective/Rationale:
These studies will validate the enzyme kynurenine 3-monooxygenase (KMO) as a target to develop drugs to treat PD (PD). KMO is expressed in cells involved in inflammation, which is increased in Parkinson’s disease. When active, the enzyme produces molecules that are toxic to nerve cells. We will use inhibitors of this enzyme that reduce the toxic molecules and increase the production of protective molecules in brain.
Project Description:
Our laboratory has shown that a pre-clinical model of PD, over-expression of alpha-synuclein reproduces many symptoms and pathological features of the disease. We will test the efficacy of the KMO inhibitor to block progression in the pre-clinical model. We will administer either drug or “placebo” to the model over several months and determine whether those that receive the drug fare better in behavioral tests that assess their olfactory and motor function than those receiving placebo. At the end of the experiment, we will which group retained more dopamine, the chemical lost in PD and that abnormally decreases in the pre-clinical model.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The inhibitor of KMO that we will use can be given orally and has been shown by our collaborator, Dr. Paul Muchowski from the Gladstone Institute and UCSF, who has developed this drug, to improve pathology in models of Huntington’s and Alzheimer’s diseases. Therefore, there is a large effort underway to develop this drug as a therapy for these diseases. If our results show that it also improves models of PD, this will spur its development for treating PD and this effort will be accelerated by ongoing work in other neurodegenerative disorders, thus reducing the time to bring this approach to the clinic to treat patients with PD.
Anticipated Outcome:
We expect to determine whether inhibiting KMO is a valid therapeutic approach for PD based on its efficacy in a pre-clinical model that is based on a mechanism (alpha-synuclein accumulation) that occurs in patients with PD.
Final Outcome
Administration of the kynurenine 3-monooxygenase inhibitor (KMOI) JM6 to pre-clinical models over-expressing alpha-synuclein for 12 months (ages 2 to 14 months) significantly increased kynurenic acid levels in brain, the expected biochemical effect. These results confirmed that the drug acted as predicted based on previous studies in models of other neurodegenerative diseases. Treatment with JM6 improved deficits observed in 14 months old mice on challenging motor tasks, decreased the progression of motor deficits towards parkinsonism, and slightly increased the size of alpha-synuclein aggregates, which might be protective. However, it failed to reverse the small deficits in dopamine and synapses that emerge at 14 months in these mice. Overall, the behavioral effects were modest despite a trend towards improvement, suggesting that KMO may be a valid target for Parkinson’s disease but that higher doses or a more potent drug may be necessary to induce clinically significant benefits.