Executive Summary

There is a significant unmet need for human models for risk assessment that can be utilized for drug optimization in early development. Clinical safety failures are only predicted by nonclinical studies 25% of the time because of (1) lack of predictable in vitro models; (2) rodents show low concordance (42%) with human clinical outcomes; and, (3) non-human primates are more predictive, but limited by cost, throughput, and ethics.

Historically, cell cytotoxicity assays are conducted using model cell lines that that are useful for characterizing non-specific drug toxicities at high doses.  Intestinal off-target effects are the most common adverse events in Phase I clinical trials and often reflect biology specific to the GI tract, which are not represented in common cell lines. 

Altis’ RepliGut® Planar model is a unique in vitro model of the intestinal epithelium, which provides a critical barrier against luminal pathogens and is essential for efficient nutrient absorption. A damaged gut epithelium can lead to rampant negative systemic effects, so understanding the toxicity of compounds is essential prior to in vivo trials. The RepliGut® Planar model provides a physiologically-relevant, primary-cell derived intestinal epithelial monolayer that can be used to investigate cell health through a variety of established read-outs, including assays focused on barrier function, cytokine secretion, and gene and protein expression.

RepliGut^® tissue constructs have the potential to address critical needs in pharmaceutical drug development. Based on human intestinal stem cells, RepliGut^® eliminates the issues associated with the use of immortalized cells lines, such as Caco-2. The polarized monolayers express tight junction proteins and recapitulate the barrier function of the intestine in vivo. Additionally, RepliGut^® monolayers express all of the major cell lineages found in the intestinal epithelium. Because RepliGut^® uses healthy, normal (not cancerous) human primary cells, they provide more physiologically relevant results. Intestinal stem cells used for the RepliGut^® system are harvested from transplant-grade human donor tissue for which there is no recipient match. As such, the stem cells are very high-quality with extremely low necrotic or ischemic damage.

The form factor for the platform is an SBS format multiwell plate with Transwell^® inserts, and the platform can be used in 12 or 96-well plate formats, so it is high-throughput and easily integrated into standard laboratory equipment and workflows. Luminal and basal reservoirs allow compounds and additional cell types to interact with the epithelial cells for side-specific assays.

With this design, RepliGut^® can more accurately model different behaviors in the intestine, such as the barrier function. Altis’ goal is to reduce the time and cost of drug development, as well as reduce the need for animal testing.