Why do so many preclinical PD studies take place in mice instead of rats? Is one species preferred over the other?
There are a lot of practical reasons to choose one species over the other, including which one has better PK data or detailed archived data. If a transgenic or knockout model is needed, mice are preferred because more transgenic mice are available than transgenic rats and knockout models are only developed in mice. Conversely, certain rat models (AAV-alpha-synuclein) are more richly characterized than corresponding mouse models. For example, the 6-OHDA rat model is more popular than the MPTP mouse model, because the 6-OHDA model is more stable and supports robust efficacy studies.
Is it possible to detect fine motor differences, such as gait width or interlimb coordination, unilaterally in the 6-OHDA model?
Yes. Unilateral differences can be detected using the cylinder tests and there is a high degree of confidence that the MotoRater test can detect unilateral differences.
How are animals walking on the platform tracked and analyzed?
The animals are marked and, as they walk on the platform, the camera picks up the marks and translates them to stick figures, which are then analyzed by proprietary software.
Has Charles River generated data to support predictive validity using pharmacological agents such as A2A antagonist and standard dopaminergic treatments in the MotoRater test?
Predictive validity is defined as data consistent with clinical findings. Currently, there is a great deal of focus, both at Charles River and in the field, on A2A antagonists that are predictive of target engagement (6-OHDA turning) and efficacy (cylinder tests and fine motor tests). Interestingly, A2A antagonists tested in the cylinder test and MotoRater test show similar modest effects as A2A antagonist tests in large animal studies. Therefore, we can conclude that the studies that we have done so far have predictive validity in non-rodent studies and clinical trials.
Has the MotoRater test been validated with clinically used PD therapies (L-DOPA or DA agonists)?
Showing that the PD models are responsive to L-DOPA or DA agonists using the MotoRater test is essential to its validity. We are in the process of completing that work and building that dataset.
Do you need a minimal speed and/or the same speed for all animals to calculate the gait impairment?
No. Gait impairment is studied by using stride length (distance between the paws), which is independent of gait speed.
Does gait impairment evolve over time in alpha-synuclein mice?
No. Once steady state is reached, the effects of the brain are fairly stable so there are no more significant changes in gait impairment.
Do the lesions of the AAV-alpha-synuclein (AAV-α-syn) rodent models reflect those of human PD and are these reported?
Yes. The effects on dopamine and Lewy bodies suggest that the lesions in the AAV-α-syn rodent models reflect those of human PD. However, because the human α-syn is introduced into a rodent model, it is not a one-to-one comparison. Human PD patients have increased α-syn, which is also a major component of Lewy bodies. Unlike model that target dopamine directly (such as the 6-OHDA and MPTP models), the AAV-α-syn rodent models show accumulation of α-syn beyond the striatum and substantia nigra, resulting in a more complete phenotype of the disease state. This model better recapitulates the human condition, including behavioral changes, than the 6-OHDA or MPTP models, which focus on a specific part of the disease.
If you have additional questions, feel free to contact us.