Following Axol Bioscience and Censo Biotechnologies recent merger to form Axol Biosciences, our CSO Ashley Barnes was
invited to speak at the Neuroimmunology Drug Development Summit
alongside other experts from academia and industry on the advances being
made in this burgeoning field.
In his talk Ash explained how the combined entity of Axol and Censo is better positioned to be a comprehensive solution provider for R&D and assay development groups working to advance understanding and drug development for neuroimmunological conditions. Axol has long been serving the neuroimmunological market by providing performance proven ready for use microglia and astrocytes. The Censo scientific staff bring a deep breadth of immunology expertise and experience in assay development and modeling of inflammation and immunological models.
After his talk Ash took some time to describe the power of induced pluripotent stem cell (iPSC)-derived astrocytes and microglia in neuroimmunological research applications.
Below are his answers to some of the pressing questions that arose from the audience and the field.
1. Why are human iPSC-derived Astrocytes and Microglia good models for neuroinflammation?
There is ever increasing data on the important role of astrocytes and microglia in maintaining the homeostasis and health of neural pathways. Although the neurons are the primary effector cell, the support network cells, and their dysregulation are of great interest in finding therapeutic interventions for diseases like Alzheimer’s Disease (AD).
Of particular focus is the role of Triggering Receptor expressed on myeloid cells 2 (TREM2), a receptor expressed by microglia. It has recently been shown in mice that loss of function mutations in Trem2 in Alzheimer’s Disease models with beta-amyloid pathology can advance the rate of brain atrophy.
Due to the scarcity of primary human CNS tissue, iPSC models are important tools to help assay development and R&D in drug discovery. The extensive datasets we are accumulating at Axol Biosciences from functional assays that probe the phagocytic activity, cytokine release and
chemotaxis of our microglia, alongside mRNA profiling, provide robust
assays by which to test compounds or mutant cell lines.
The functional differences we see in different genetic models shows the value and relevance of the cellular models we provide. For example, we have observed a distinct dysregulation of chemotaxis and phagocytosis in some of the TREM2 mutant microglial cell lines we offer (Figure 1).
Figure 1. TREM2 and CD33 gene edited isogenic lines used to model Alzheimer’s Disease
A) Heatmap of transcriptomic analysis of all lines demonstrates some differences between all lines. Functional analysis for B) IL6 cytokine release following 24 h stimulation with LPS (n=3) and C) phagocytosis of beta-amyloid (1-42) at 24 h (n=3). Credit: Axol Biosciences.
2. What inflammatory conditions and diseases can we model and assay?
When validating our cells, we have focused on functional assay formats synonymous with immunological functions such as: chemotaxis, cytokine release and phagocytosis. This allows for a greater understanding of infectious diseases, including COVID-19, which have always had secondary and long-term effects that have been overlooked because unlike the other dementia diseases, the acute symptoms during viral infection have been the primary areas of concern.
A recent paper in the Lancet showed that 34% of patients infected with COVID-19 will suffer mental health and neurological conditions in the 6 months following infection. These symptoms are likely caused by neuroinflammation.
I believe that Long-Covid and chronic fatigue syndrome will become an increasing area of focus and the use of iPSC reagents will be a valuable tool for researchers in this space to understand the pathways that have become dysfunctional.
3. What are the limitations of iPSC-derived cells to model neuroinflammation and how can these be overcome?
One of the most significant limitations is how scientists are modeling disease in the dish. Diseases are multifactorial and involve many different cell types, so testing compounds on mono-cultures of cells can only reveal so much about a disease process. To understand the interactions between different cell types in physiological and disease states, a more complex model is needed. In our labs we routinely use co-culturing methodologies to grow two, three or four different cell types in a dish to make our models as disease relevant as possible.
For example, it is possible to seed microglia with beta-amyloid to activate them before co-culturing
them with astrocytes and/or cortical neurons. We can then test our
customers’ compounds or cell lines in this more physiological scenario.
This type of approach could also work for frontotemporal dementia models if we seeded our microglia with Tau aggregates or ALS models if we seed with TDP43 to astrocytes.
The other limitation is patient specificity. It is known from GWAS studies that mutations in the TREM2 gene locus is
a risk for Alzheimer’s Disease. However, getting tissue from a patient
that carries mutations in this or other Alzheimer’s genes is difficult
as not every patient has their genome sequenced or agrees to have their tissue being used
for research purposes. We can do a lot to recapitulate the disease
phenotype through CRISPR gene editing of our lines, but more outreach
needs to be done from a patient advocacy perspective to get tissue from
donor patients. Having said that, we do work with patient advocacy
groups for rare diseases, and we have been able to make stem cells from
4. What are your hopes for the future of neuroimmunological R&D and how can Axol help scientists achieve these goals?
I hope that following the presentation of our data that other groups can see where our products and services can help in their discovery work and help build ever better models of the diseases they are focused on.
Watch Ash's talk from the conference