Focus Area 1: Unraveling Inter-Epithelial Crosstalk in Health and Disease
Projects:
- Emulating the skin-lung crosstalk in the context of atopic diseases
Atopic dermatitis (AD) is the most common inflammatory skin disease worldwide. Currently, 25% of children and 3-5% of adults are affected. AD often heralds the onset of other allergic diseases such as food allergies, allergic rhinitis, and allergic asthma, in what is known as the atopic march [5]. It is estimated that between 30-50% of children with moderate-to-severe AD will undergo the atopic march and eventually develop allergic asthma. The underlying mechanism are largely unknown. Nonetheless, compelling data indicate that AD and asthma are causally linked which implicates a skin-lung crosstalk. So far, investigating the atopic march has been hampered by the lack of suitable models [6, 7].
To overcome this limitation, my lab has developed skin disease models that closely emulate characteristics of AD in vitro [8-11] using either AD-patient-derived cells [8, 9], RNA interference, or co-cultivation with AD-specific interleukins such as IL-4 and IL-13 as well as CD4+ T cells [13, 14].
Based on previous results, our current hypothesis is that the ECM plays a central role in communicating inflammatory diseases between epithelial tissues which we are currently investigating further.
This research may pave the way towards a novel understanding of the atopic march and holds great potential for the identification of novel therapeutic targets to treat or even prevent atopic diseases
2. Unraveling the impact of the hydrogel barrier in the gut-lung crosstalk (Project A06 in Collaborative Research Center 1449)
While being anatomically distinct, potential anatomic communications and complex pathways involving their respective microbiota have unveiled the existence of a gut-lung axis (GLA). This inter-tissue crosstalk putatively contributes to healthy and diseased states. In fact, chronic lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD) often occur together with chronic gastrointestinal tract diseases, such as inflammatory bowel disease (IBD). Up to 50% of adults with IBD have pulmonary involvement, such as inflammation or impaired lung function, and patients with COPD are 2-3 times more likely to be diagnosed with IBD [19]. Further, the GLA also modulates the response to acute bacterial and viral lung infections, the latter of which has been recently highlighted through the COVID-19 pandemic.
So far, gut microbe-derived components and metabolites such as short-chain fatty acids have been identified as mediators of the GLA. Yet, mechanisms beyond the microbiome are highly likely and many questions remain as to how this crosstalk impacts lung and intestinal hydrogels and, thus potentially contributes to the manifestation of comorbidities.
Hence, we are currently developing OoC setups allowing a long-term co-cultivation of intestinal and pulmonary epithelial tissue models to emulate the GLA in a human-based ex vivo system. For this purpose, we use a plug-and-play setup, from which tailor-made OoC can be easily assembled. The OoC provides a variety of ultra-compact cell culture modules, micropumps, valves, reservoirs, mass exchangers, and sensors that can be combined individually. This allows full control over flow rates and nutrient concentrations for each tissue, thus ensuring need-based supply. A pneumatic pump is implemented that may also simulate bowel movement. Tissue-specific chips are integrated yielding a modular OoC setup.
Focus Area 2: Human (Disease) Models to Develop & Test Next-Generation Therapies
Gene therapies are powerful tools to prevent, treat, and cure a plethora of human diseases. The discovery of CRISPR-Cas9 in particular and its fast-paced advances significantly accelerated the genome editing field. Despite those exciting advances, the main obstacle, that currently hampers the clinical translation of gene editing, is the lack of safe and efficient delivery strategies. Viral vectors are limited by their extremely high manufacturing costs, the inability to re-dose, and emerging safety concerns.
Combining genome editing with non-viral delivery systems such as lipid nanoparticles (LNP) has the potential to overcome these limitations. However, assessing the delivery and therapeutic efficacy in animal models again poorly predicts the human situation due to distinct inter-species related anatomical and (patho)physiological differences. For example, it is significantly easier to deliver genes into rodent skin or lungs since they possess much weaker epithelial barriers than humans.
We aim to close this gap by leveraging human (disease) models that much better recapitulate human biological barriers and, hence, more reliably predict the performance of the delivery systems in vivo.
Also, the current focus in gene therapies lies on systemic or ex vivo applications, and comparably little attention has been dedicated to epithelia including the skin or the lungs. In both cases, systemic administration of genetic cargo will not result in intra-epithelial delivery. In fact, the lack of vasculature in the epithelial tissue and tight epithelial junction zones prevent the delivery or penetration of biomacromolecules. Consequentially, enabling gene editing in skin or lung epithelium, either a treatment of cells outside of the human body (ex vivo approach) followed by a re-grafting, or a topical, in situ application.
To overcome these limitations, we utilize our expertise in topical drug delivery and human disease models to develop and harness CRISPR delivery strategies to the skin and the lungs. Our target diseases are rare monogenic diseases such as congenital ichthyosis for the skin and cystic fibrosis for the lung.
