Gene TherapyOrganoids
Translational Organ Models
Sarah Hedtrich
The Hedtrich Lab strives to understand and tackle inflammatory and genetic diseases of human epithelia with a current focus on skin, lungs, and intestine. As we firmly believe that human-based models are critical to close the current translational gap in biomedical research, my lab’s research relies on complex human-based organ- and organ-on-chip (OoC) models, rendering the development and validation of those my lab’s overarching theme. We then harness them (1) to unravel disease-related pathomechanism with a current focus on inter-organ crosstalk and (2) to develop and test next-generation therapies. Our interdisciplinary research requires close collaborations with clinicians, chemists, engineers, and experts of many other life sciences disciplines.
Overarching Theme: Bioengineering Complex Human (Disease) Model
Animal models, particularly rodents, are still the gold standard in basic and preclinical research. However, biomedical research is currently undergoing a paradigm shift towards human disease model-centered approaches. This shift has been driven by the notoriously high failure rates of the current drug development process. Although investments increased at unprecedented rates over the past decade, the drug attrition rate hit an all-time high of 95% in 2021. Most drugs fail in clinical stages despite proven efficacy and safety in animal models.
Different reasons account for this translational gap, one of them being that the decision on a drug candidate’s entry into clinical trials relies almost exclusively on animal-derived data. Poorly characterized animal models, a lack of experimental rigor and quality control, but also distinct interspecies-related differences between animals and humans contribute to the high failure rate in clinical trials.
For example, in dermatological research, mouse models are predominantly used despite merely 30% overlap of skin-associated genes between men and mice [4]. Overall, most animal models are especially poorly predictive when studying (patho)physiological aspects of human epithelia. For instance, mice normally do not develop atopic dermatitis (AD) and an atopic march, but still, these are the most frequently used animal models.
This disconnect expands to many other areas including COVID-19, which we recently discussed in an article published in Nature Reviews Materials and Nature Reviews Bioengineering.
To mitigate this limitation, my lab is engaged in the development of complex human (disease) models.
We have successfully developed and utilized organ models of the skin, the lung, and the intestine. A few years ago, we moved into the organ-on-a-chip (OoC) field and now have a fully established microfluidic OoC setup, which we use to study inter-organ crosstalk in healthy and diseased states (see Focus Area 1).
We currently work on the implementation of adaptive and innate immune functions while striving for maximal biomimicry (Fig. 1).
Main activities include bioengineering of lymph node-like tissues, generating multicompartment lung models that allow the application of (patho)physiological breathing mechanics, and establishing multi-OoC cultures for in-depth studies of interorgan crosstalk.
In addition, we are increasingly interested in developing iPSC- and ASC-derived (disease) models aiming for the generation of autologous tissue and multi-OoC setups which we will utilize to guide treatment decisions and to aid patient stratification.
Akkordeon
