Testing of Ambroxol in the Thy1-Alpha-Synuclein Pre-clinical Model of Parkinson's disease
Therapeutics Development Initiative, 2011
Biochemical evidence suggests that blocking the maturation of a natural enzyme, glucocerebrosidase (GCase), can cause the build-up of alpha-synuclein deposits in neurons.† Such deposits are pathological hallmarks of Parkinsonís disease.† Compelling genetic evidence has also implicated GCase in Parkinsonís disease.† Ambroxol is an existing drug that can ďchaperoneĒ GCase to its mature form where it no longer promotes pathological deposit formation.† We intend to test whether ambroxol can ameliorate Parkinsonís disease-like symptoms and pathology in a pre-clinical model of Parkinsonís disease.
Thy1-Alpha-Synuclein pre-clinical models have been genetically engineered to ďover-expressĒ the alpha-synuclein gene in the brain.† These pre-clinical models recapitulate during their growth and development a number of motor, non-motor, and neuropathological deficits characteristic of Parkinsonís disease.† We will feed the pre-clinical models ambroxol and periodically test them for improvements in Parkinsonís disease-like deficits Ė this will include measuring motor skills such as balance and coordination, and testing for olfactory dysfunction and cognitive deficits.† Results with ambroxol-fed pre-clinical models will be compared with results of identical tests on ďcontrolĒ Thy1-Alpha-Synuclein pre-clinical models that have not been fed the drug.† At the end of the experiment, the brains of both ambroxol-fed and control pre-clinical models will be examined for neuropathological signs of Parkinsonís disease such as alpha-synuclein deposits, dopamine depletion, and inflammation.
Relevance to Diagnosis/Treatment of Parkinsonís Disease:
Parkinsonís disease is a very complex disease and has traditionally been treated with therapies aimed at treating the symptoms rather than the underlying causes; this is understandable since so little is known about the actual causes.† Recent research has indicated that GCase deficiency may be a fundamental contributing factor to Parkinsonís disease, thus intervening to correct such a deficiency using pharmacological chaperones like ambroxol might represent a new and powerful therapeutic approach.
Our goal is to re-purpose ambroxol as a drug for Parkinsonís disease (ambroxol is currently used to treat airway disorders).† Positive efficacy data in the Thy1-Alpha-Synuclein pre-clinical would motivate and support efforts to move forward with clinical trials of ambroxol in Parkinsonís disease patients.† Demonstration of efficacy in Parkinsonís disease patients will likely lead to ambroxol being approved as a therapeutic for Parkinsonís disease.
Location: Monmouth Junction, New Jersey, United States
Location: Los Angeles, California