Neurodegenerative diseases (including Alzheimer’s Disease (AD)) are characterized by the progressive and debilitating loss of nervous system function and control. They currently affect tens of millions of patients worldwide and, with our aging population and increasing comorbidities, rates of these conditions are rising.
There is a clear need for new therapies. While animal models have provided valuable insights, researchers are looking to use more human-relevant models to close the translational gap that has seen new therapy failure rates as high as 99.6%. In light of this, here is what Tessara Therapeutics had to say about the work they do to contribute to this industry-wide effort and the significance of their recent collaboration with Axol.
Who are Tessara Therapeutics and what do you do?
Tessara Therapeutics are a small biotech company based in Melbourne, Australia who have developed the RealBrain® Technology, which provides a unique platform that has allowed us to develop a variety of 3D human cell-based brain models. These 3D neural tissues are often called “mini brains in a dish”. We have taken this mini brain in a dish concept and commercialized it into a 96 or 384-well plate format that is well suited for drug screening.
Our goal as a company is to accelerate drug discovery and develop better therapies for neurological diseases. Having a robust, reproducible model that recapitulates the complexity of the human brain to do pre-clinical screening of compound libraries will also save millions of dollars by reducing the rate of failed clinical trials, which commonly result from poor translation of animal data.
What differentiates RealBrain® from other 3D cell-based models such as organoids or spheroids?
Whilst organoids and other 3D culture systems have many advantages (e.g. increased complexity) over traditional 2D cell cultures, they are also associated with a number of well-known practical compromises. Tessara’a RealBrain® Technology was designed to address many of these issues and has a number of key differentiating features, as follows.
- Quick (3 weeks) maturation using one simple media formulation and a single starting cell population that gives rise to a complex network of neural and glial cells. Competing technologies require many more weeks or months of maturation before being ready for use, and often require the seeding of multiple cell populations, complex media formulations and the use of other exogenous factors
- The permeability of the micro-tissues supports long-term viability (>4 months) for chronic experimentation using only standard culturing protocols. Competing technologies are often only viable for several weeks and may often develop “necrotic cores” due to limited perfusion of nutrients throughout the tissue
- Optically clear with tuneable cell density– “The Best” 3D neural tissue for (high content) imaging. Competing technologies often have quite a high cell density/neural architecture that requires tissue clearing and/or sectioning and which precludes easy imaging and analysis
- Automated manufacturing has been optimized to provide reproducible and scalable production. Competing technologies often have complex production and maturation cycles that are very difficult to automate
You recently worked with Axol Bioscience to produce a body of work presented in the poster “Development of iPSC-derived 3D human brain micro-tissues for drug discovery applications”, what brought about this collaboration and what was its significance?
Axol Bioscience came into the picture, as they are an industry leader and have a large number of iPSC and patient-derived cell banks readily available, thereby affording us the opportunity to create 3D human micro-tissues that recapitulated the diversity of genetic backgrounds seen in neurodegenerative diseases. Axol Bioscience manufactures these cells and supporting media and supplements at scale under ISO 9001 accredited conditions.
The collaboration with Axol is significant as we have demonstrated proof-of-concept for the generation of iPSC-derived human 3D micro-tissues using cells sourced from both healthy donors and patients with familial Alzheimer’s disease. This work will pave the way for the development of protocols for “clinical trial in a dish” studies to help accelerate personalized medicine approaches for neurological conditions and will help drive innovation and knowledge translation.
It will also significantly de-risk drug discovery pipelines by reducing costs and providing earlier insights into drug neurotoxicity and therapeutic efficacy. With current changes in the regulatory landscape, this work will also accelerate the adoption of non-animal-based screening approaches across the sector.
Given the critical role of data in validating and advancing technologies like these, do you have data available that demonstrates the physiological relevance of your system?
We have worked with a number of partners to demonstrate key features of our platform that support its physiological relevance. Examining the genetic profile of our micro-tissues, for example, has demonstrated that they are consistent with gene profiles from human brain; furthermore, unlike 2D cultures grown using the same human brain cells and culture conditions, the genes expressed in our platform retain their neural identity whereas in 2D the genetic profile is representative of tissues from all over the body. Most importantly, these discoveries have been independently validated by a global major CRO that performed an evaluation study with our model, and we’ve engaged in further evaluation and commercial discussions. Our profiling also reveals significant expression of genes in pathways related to axon guidance, growth/development and neurotransmission, highlighting the presence of neurotransmitter receptors that drugs use to evoke their activity. We are also developing our own database that characterises the efficacy of compounds in our models (including known chemicals, tool compounds and drugs used both in the clinic and clinical trials). Current testing has already highlighted a number of examples where our model has predicted human toxicity and also where it has discriminated between the effects of a compound that had divergent effects in animal and human testing.
Furthermore, in our poster we highlight data from our Alzheimer’s disease model. The ADBrain™ micro-tissues model key pathological features of the AD brain including; Aβ42 deposition, loss of neural networks, hyperphosphorylated Tau, and dystrophic axons. The ADBrain model is also more susceptible to cell death as compared to the healthy brain, as we show in the poster. Specifically, we demonstrate that the ADBrain™ has increased susceptibility to ferroptosis-induced cell death as compared to the healthy control brain (ferroptosis is a distinct mode of cell death characterized by iron-dependent accumulation of lipid peroxides and is implicated as a mechanism of neurodegeneration in AD and other indications). This is one example highlighting the physiological relevance and utility of this platform. You can download the poster here to see more.
