TissUse awarded with funding in the 2019 CRACK IT Challenges competition!

About the challenge

The National Centre for the Replacement, Refinement and Reduction of Animals in Research (NC3Rs) is a UK-based scientific organization that has been hosting the CRACK IT Challenge since 2011. This challenge-led competition funds collaborations between industry, academics and SME’s to improve business processes and the development of commercial products that will have a significant scientific and 3Rs impact. [2]

In 2019, three topics were offered including one called CleanCut – ‘Establishing an in vitro model to assess the safety of genome edited human haematopoietic stem cells, which is sponsored by Bayer, Novartis and Takeda. Now, as one of three teams, TissUse has progressed to Phase 1, using it’s HUMIMIC Multi-Organ-Chip System to develop an in vitro model to replace in vivo tumorigenicity studies for the safety assessment of genome edited human haematopoietic stem cells. The winner of Phase 1 might then proceed to the next step in Phase 2 which is lasting up to 3 years and offers funding for up to £ 1 million. [3]

In the end, the multi-organ-platform should include bone marrow, lymph node (or a suitable alternative) and possibly a third organ (liver, spleen, brain, or lung) and permit circulation of hHSCs. While the main focus lies on leukemic cell proliferation within the bone marrow equivalent and infiltration into the target organ, other processes concerning the hHSCs will be monitored closely. The final model should provide increased predictivity over the current in vivo and in vitro models. [4]

The addressed diseases

The major dieseases that will be addressed include sickle cell anaemia, haemophilia and thalassemia. They are blood-related monogenic diseases, whose origin lies in a single gene modification leading to malformed haemoglobin structures. The CRACK IT Challenge states that “The only curative treatment is an allogenic haematopoietic stem cell (HSC) transplant, which involves transferring HSCs from a healthy donor to the patient’s body after high-intensity chemotherapy or radiation.” However, the downsides for the patients are the expenses and the lifelong pharmacological immunosuppression. [4,5]

To address this, a potential curation is promised by genome edited hHSCs. By using ex vivo gene modifying methods like CRISPR/Cas9, the patient’s disease-causing gene modifications could be repaired, thereby directly addressing the disease’s origin. Despite the high level of precision of these methods, unexpected modifications could occur which might lead to cells with oncogenic potential. Because of that, genome edited cells need to be broadly assessed for safety liabilities prior to their use in the clinic. [6]

Replace in vivo studies

To assess the tumorigenicity of genome edited products, the regulatory requirements still demand for in vivo studies. Only in vivo experiments show the actual consequences of mutations that before could only be predicted by in silico tools and current in vitro cell culture models. [7]

However, these studies are lengthy, costly and are not always predictive of the risk to human safety. The reason is that engraftment with human cells in the animals is not always successful. This means that a few hundred immunocompromised mice are dosed but do not provide useful data, therefore requiring studies to be repeated. [8]

We are looking forward to meeting the CRACK IT Challenge’s aim that “[t]he assay could also be used to identify appropriate dosing regimens and assess the toxicity of new compounds impacting haematopoiesis”. [4]

As a company providing Multi-Organ-Chip solutions as a completely new approach to replace laboratory animal testing, it is important for us to make every effort to successfully complete the CRACK IT challenge. We are looking forward to working on a highly predictive in vitro assay, thereby replacing in vivo tumorigenicity studies and reducing the need of rodents to predict GE-hHSC impact on human safety.