*BARRY BEDELL

Inducible Mouse Models to Accelerate Drug Development for Parkinson’s Disease and Other Synucleinopathies

Challenge: Parkinson’s disease (PD) is characterized by motor symptoms, cognition, speech, mood, and behaviour disorders. While PD is currently diagnosed based on motor impairment, the non-motor deficits (the prodromal stage) typically precede the motor symptoms by several years. PD is associated with the presence of Lewy bodies and neurites composed of misfolded fibrillar α-synuclein. The recent development of animal models of α-synucleinopathy allows preclinical assessment of putative “anti-synuclein” therapies. However, non-invasive imaging of these models is lacking.

Solution: Biospective and InviCRO combined their complementary expertise in the field of medical imaging to develop a new mouse model to characterize early, PD-related pathological changes associated with the olfactory system in mice. To provide well validated tools to accelerate the development of disease‐modifying treatments for PD, the team used multi‐modality and imaging techniques such as in vivo MRI and quantitative immunohistochemistry. The diffusion MRI and MEMRI data showed that the injection of α‐synuclein preformed fibrils (PFFs) in wild type (WT) mice induced structural and functional changes. Injection of PFFs into the anterior olfactory nucleus (AON) led to α‐synucleinopathy in anatomically‐connected olfactory regions in these animals. Injection of human PFFs in transgenic (Tg) animals over-expressing human alpha-synuclein with the familial A53T mutation also led to synucleinopathy. In both models, PFFs spread from the ipsilateral to contralateral side of the brain. Four months post‐injection, WT and Tg mice expressed significant amount of PFFs into the olfactory bulb and the AON, which was associated with olfactory deficits.

Achievements/Impact: This project led to the development of an inducible mouse model of α‐synucleinopathy. This approach allows for a comprehensive understanding of the alterations underlying in vivo MRI‐based imaging biomarkers. This rapid, robust, inducible model can be used for preclinical studies to accelerate the development of disease‐modifying treatments for PD and other synucleinopathies.

Principal Investigators:

Barry Bedell
Biospective

Jack Hoppin
InviCRO (USA)

Completed Project
$1,184,000 / 3 years
Supported by CQDM through:
• MESI
And by co-funding partner:
• MLSC