In Vitro Models To Advance Preclinical Drug Development
Assays mimicking human tissue environments play a crucial role in accelerating the drug discovery process.
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The field of preclinical drug development has seen remarkable advancements in recent years, particularly in the development of in vitro models. Such models are helping to bridge the gap between preclinical studies and clinical outcomes by improving the predictability of human responses to drug candidates.
Technology Networks recently spoke with Dr. Emanuela Costigliola, chief marketing officer at Newcells Biotech, to learn more about the development of two new assays, advances in preclinical drug development and the significance of physiologically relevant models in predicting human responses.
For those not familiar with your work, could you explain the broad aims of Newcells Technology?
Emanuela Costigliola, PhD (EC):
When talking about Newcells’ technology, we are referring specifically to the functional and predictive in vitro models of kidney, retina and lung that we have developed from induced pluripotent stem cells (iPSCs) or primary cells, together with the assay that we run on them. These have been developed to provide customers who are at the preclinical development stage with data that allows them to confidently assess and accurately predict the safety and efficacy of their compounds in vivo, thus accelerating clinical translation and improving the success of their clinical trials.
Because of the specific structure and functional validity of these models that very closely mimic the in vivo environment, the assays that we run (efficacy, safety assay, disease modeling, drug–drug interactions, transporter or cross-species studies) are predictive of the results that our customers are likely to see in vivo. This allows for rapid screening of their lead compounds or even assessment of gene therapy viral vectors, maximizing the chances of success of their lead compounds in vivo, i.e., avoiding vivo failures, which can be very costly in development.
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The design of this assay has resulted from the industry’s need for a robust, rapid and high-sensitivity way of measuring cilia activity. This is important, for example, to be able to assess the efficacy of compounds on mucociliary clearance in chronic obstructive pulmonary disease (COPD) or asthma-like conditions or to assess the safety of chemical compounds in the airways.
This assay addresses all of those points, allowing for the accurate measurement of the effect and safety of compounds and airborne chemicals on the function of ciliated cells within the lung’s small airways.
The ciliary beat frequency analysis assay, first of all, is based on our physiologically relevant and established small airway epithelial cell (SAEC) model, meaning that the output dataset is a reliable prediction of clinical translation and, equally importantly, it harnesses Newcells’ proprietary CiliaBeat software which allows the capture of data:
- in a rapid timeframe – meaning we can measure the effect of fast-acting drugs.
- at high sensitivity (as low as 0.25 Hz) – meaning even the slightest toxicity or low dosing effect will be detected.
It also provides rapid and unbiased analysis of large datasets in an easy-to-read format – meaning it allows for rapid decision-making with accurate in-depth data.
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Our models are functional, physiologically relevant and therefore predictive of what will happen in vivo. They are iPSC or primary cell-based derived.
Our 3D neural retinal organoids, for example, are derived from iPSCs and can be developed from healthy or diseased lines. We can also derive retinal pigment epithelium (RPE) cells from the same line, meaning that the customer has isogenic controls. They are unique in that they have a stratified microarchitecture that contains all the relevant cell types, including active photoreceptors sensitive to light stimuli, and they have been successfully used to test for drug toxicity and gene therapy vector efficacy and localization.
Similarly, for example, our kidney proximal tubule cells (PTC) model expresses high levels of all relevant basolateral and apical transporters involved in drug handling and clinically relevant biomarkers of toxicity.
Our lung SAEC model is an air-liquid interface model that comprises all key cell types and a functional epithelial barrier and can reliably mimic disease-like conditions. Our fibroblast model has been specifically optimized for use in our high-throughput high-sensitivity fibroblast-to-myofibroblast transition assay with proprietary reagents that increase sensitivity and leverage our imaging capabilities.
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EC:
The number one challenge we are aiming to solve is the limited physiological relevance to the human environment and, therefore, the lack of predictivity of current in vitro as well as in vivo models. This also goes with the impracticalities and costs that come with the use of animal models. Animal models, for example, suffer from low sensitivity to renal toxicity. This is one of the reasons we have a PTC model from multiple species, so that cross-species experiments are also possible, in vivo results can be explained and the best in vivo model selected.
Another challenge that the industry is facing with cell lines is the lack of interactivity between cell types, which we solve with our complex and functional models where we see multiple functional cell types, for example, in retina and lung models or functional transporters in the kidney PTC model.
There is then always the issue of tissue availability, such as in the retina where tissue explants are rare to come by and have a limited window of use. The same goes for the kidney, but we see this being less of a problem. With the retina, we are also addressing the issue of having isogenic controls of the neural retina and RPE.
By enabling close mimicking of disease states like COPD, and in the case of retina models, the actual development of a diseased model, these models and assays allow reliable evaluation of compound efficacy.
Finally, there is always the challenge of sensitivity and data analysis. We have looked at and addressed this with our capabilities, along with our new imaging suite, and developed assays that are highly sensitive and, in some cases, also allow for high throughput. As an example of this, our ciliary beat assay enables the screening of compound libraries for toxicity and efficacy in a very accurate and rapid way, maximizing the possibility of all potentially active compounds being brought forward and maximizing the safety potential when a compound translates to in vivo.
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The aspiration is for these models to expand in their applications, for example, gene therapies, and to continue to inform and accelerate IND approvals of compounds and accelerate access of safe therapies to patients, minimizing the need for in vivo studies.
We are not at the point yet where these models can fully replace in vivo testing, but we are going in that direction. The more we manage to prove that data is translational to the clinics, the more the regulators will accept this data to progress through phases, as we are already seeing happening.
The long-term aim is to get to the next generation of those complex, predictive models where we can confidently mimic a whole organ and assess the effect of compounds on various parts of it.
