Several classes of mammalian models of α-synucleinopathy are available for use in drug development. These include transgenic models and models based on delivery of α-synuclein protein (such as preformed fibrils (PFFs) or extracts of Lewy bodies from post-mortem human tissue) or α-synuclein-encoding genes (for example, using adeno-associated viruses (AAVs)).
These models are being applied to assess efficacy, inform dosing and define therapeutic windows of potential new treatments.
The AAV models stand out as drug development platforms as, to date, they are robust and amenable to medium-throughput evaluation and can be used in multiple species from mouse to rat to non-human primate (NHP). The transgenic and PFF models may prove important for longer-term evaluation of evolving symptoms and for examining pathology in multiple systems, whereas the Lewy extract models are not in a position for widespread use, as patient material will differ between experiments, and duration to reach end points, so far, exceeds a time frame for relatively rapid screening of candidates.
AAV NHP models are especially well suited as a final stage before initiating clinical development, not only for evaluating the efficacy of a treatment and the clinically relevant measures of target engagement, but also for defining the therapeutic index of a candidate in a species best able to predict effects anticipated in human.
Navigating the choice of different models available is often difficult. However, with the understanding of the mechanism of action of the proposed treatment, along with consideration of potential species interactions, one can now rationally define a development plan that uses available models most optimally to advance through the preclinical space.
A major challenge in Parkinson disease (PD) will be to turn an emerging and expanding pipeline of novel disease-modifying candidate compounds into therapeutics. Novel targets need in vivo validation, and candidate therapeutics require appropriate preclinical platforms on which to define potential efficacy and target engagement before advancement to clinical development. We propose that α-synuclein (α-syn)-based mammalian models will be crucial for this process. Here, we review α-syn transgenic mouse models, viral vector models of α-syn overexpression and models of 'prion-like' spread of α-syn, and describe how each of these model types may contribute to PD drug discovery. We conclude by presenting our opinion on how to use a combination of these models through the late-stage preclinical, proof-of-principle investigation of novel therapeutics.
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L.V.K. holds a Canadian Institutes of Health Research (CIHR) Clinician-Scientist Award.
J.B.K. and J.M.B. have equity stakes in, and have received consultancy fees from, Atuka Inc., Toronto, Canada, a contract research organization that provides services using some of the animal models discussed in this Review.
Slowness of movement and decrement in amplitude or speed (or progressive hesitations or halts) as movements are continued.
(MPTP). A neurotoxin that, when injected into most animals, will produce a selective lesion of the dopamine system that can be used to model nigral degeneration.
Sialic acid-containing glycosphingolipid differentiated by the structure of its carbohydrate chains. Gangliosides are primarily localized in plasma membranes and have prominent roles in various cell functions.
- Protofibrils, fibrils and oligomers
Different α-synuclein conformers associated with the pathogenesis of Lewy body diseases, including Parkinson disease. Fibrils in particular are found in abundance in Lewy bodies.
- Rapid eye movement (REM) sleep behaviour disorder
(RBD). A parasomnia characterized by abnormal or disruptive behaviours (such as shouting, gesturing or kicking) that occur during REM sleep and are often related to dream enactment.
- Tetracycline-controlled transcriptional activation
Inducible gene expression in which transcription of a target transgene is reversibly turned on or off in the presence of tetracycline or a derivative (such as doxycycline).
Phosphorylation site associated with toxic forms of α-synuclein.
- 'Core and halo' morphology
The classical morphology of a nigral Lewy body: a spherical cytoplasmic inclusion with a hyaline eosinophilic core and a narrow, pale-stained halo.
- Morris water maze
A commonly used behavioural test for mouse or rat that assesses spatial learning and memory.
- Construct validity
The ability of a model to measure what it is intended to measure.
- Face validity
The ability of a model to reproduce the clinical and pathological features of the human disease.
- Passive immunotherapies
Exogenous antibodies specific to an antigen (such as α-synuclein) that are delivered by intravenous, subcutaneous or intraperitoneal injection.
- Active immunotherapies
Vaccinations that activate the immune system of the body to produce endogenous antibodies specific to an antigen (such as α-synuclein).
- Hybrid serotype adeno-associated viruses
Adeno-associated viruses produced to express two viral serotypes on their particle surface.
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Koprich, J., Kalia, L. & Brotchie, J. Animal models of α-synucleinopathy for Parkinson disease drug development. Nat Rev Neurosci 18, 515–529 (2017). https://doi.org/10.1038/nrn.2017.75
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