MPS disease models review: current status, opportunities and limitations
A recent review paper from members of the IQ MPS group describes the present status of microphysiological system (MPS) disease models and notable examples in six disease areas including cancer, neurodegenerative diseases and select rare diseases. Molecular mechanisms and targets for these diseases underpin potential therapies but it is current models, be they in vivo (animal) or in vitro (cellular), which many believe do not sufficiently recapitulate human disease phenotypes or the expected responses to candidate drugs.
For neurodegenerative diseases, knowledge of the biological mechanisms responsible for Alzheimer’s, Parkinson’s and ALS, for example, are often limited and this has led to an unmet need of treatments for these conditions. Factors including genetic predisposition, aging and changes in the cellular environment have been suggested as causative but the contribution of each component has traditionally been studied in animal models (e.g. transgenic mice) or isolated brain explants. These both have limitations (e.g. translation, inherent variability, lack of complex organization and poor predictivity). More effective strategies are described using MPS which integrate patient-sourced iPSC derived cells and multiple cell types such as astrocytes, microglia, neurons and endothelial cells in 3D culture.
In the case of Alzheimer’s for example, a 3D model containing human neurons, astrocytes, and microglia was developed and showed how neurons released cytokines and chemokines in response to Aß plaque formation and hyperphosphorylated tau aggregates which in turn recruited microglia, with resulting proinflammatory factor release and increased loss of co localized neurons and astrocytes. In Parkinson’s, a 3D human midbrain organoid formed from iPSC-derived dopaminergic midbrain neurons from PD patients with the LRRK2-G2019S mutation or from PBMCs of idiopathic PD patients, all exhibited key PD phenotypes. Meanwhile, treatment of an ALS-on-a-chip of 3D skeletal muscle innervated with iPSC-derived motor neuron spheroids with excess glutamic acid caused neurite regression and muscle atrophy, demonstrating the significance of the motor neuron / muscle interaction in this disease. Also, motor neuron spheroids derived from iPSCs from a patient with sporadic ALS have demonstrated fewer muscle contractions, decreased nerve fibers and neuromuscular junctions, increased TDP-43 mRNA expression and increased caspase 3/7 positive cells than control iPSCs from a healthy donor.
Overall, the paper concludes that the use of MPS platforms for disease modeling offers distinct advantages over current 2D culture systems and non clinical animal models with the industry seeing slow incorporation of these technologies into early pharmacological screening and discovery. For wider adoption of MPS, further optimization is still required, in areas such as throughput, translatability and standardization while definition of the context of use in each scenario is required as it is currently accepted that no in vitro model can fully recapitulate the in vivo environment. Ultimately, confidence in these systems will increase with more experience of these platforms, for both industry stakeholders and regulatory groups. Central to all these models is the integration of patient iPSC-derived cells within 3D microenvironments to offer better models of human disease and hence more predictive safety and efficacy data for potential therapeutic solutions.
Read the paper: View of Applications of microphysiological systems to disease models in the biopharmaceutical industry: Opportunities and challenges (altex.org)
