Bioengineering of human ossicles as advanced in vivo hematopoietic model

Project Information

hOssicle

Grant agreement ID: 948588

DOI

10.3030/948588

EC signature date 27 October 2020

Start date 1 May 2021

End date 31 December 2026

Funded under

• EXCELLENT SCIENCE - European Research Council (ERC)

Total cost

€ 1 500 000,00

EU contribution

€ 1 500 000,00

Coordinated by

LUNDS UNIVERSITET
Sweden

Periodic Reporting for period 3 - hOssicle (Bioengineering of human ossicles as advanced in vivo hematopoietic model)

Reporting period: 2024-05-01 to 2025-10-31

Summary of the context and overall objectives of the project

• What is the problem/issue being addressed?
In Europe, we estimate that over 80 million people are affected by blood disorders. Among them, blood cancers (leukemia) are by far causing the highest mortality. When at all existing, treatments are poorly effective: 92% of new drugs successful in preliminary testing fail once applied to the patient. We thus need new methods to study blood cancers and test drugs in a relevant manner.
• Why is it important for society?
The burden of blood cancer for the society is enormous. Since treatments are often non-existing or not efficient enough, most cancers are still lethal. In addition, the time and costs associated with new treatment development is substantial. Developing new technologies allowing to better understand blood cancers and test drugs in a faster and cheaper way would be of high benefit to the society.
• What are the overall objectives?
hOssicle has for objective to develop miniaturized human bone organs which can be used to study blood cancers and test drugs in a relevant manner. In fact, blood cancers emerge in our bone marrow which is contain in our bones. If we can replicate the environment in which those blood cancers naturally develop, we can better predict their behavior and compile knowledge for better treatments. This is the key objective of the hOssicle project, whereby we are using patient cells to build mini-bones define as ossicles. Within these ossicles, the patient cancer cells develop, and we can expose the tumor to various drugs and assess the efficacy of it.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

The project has led to different achievements. First, we successfully standardized the formation of human ossicles by generating a dedicated human mesenchymal line (the MSOD-B line). The MSOD-B was shown to robustly form human ossicles, capable of superior engraftment of healthy hematopoiesis, primary acute myeloid leukemia and primary solid tumors. The work has been published in Science Translational Medicine (https://www.science.org/doi/10.1126/scitranslmed.abm6391).
An additional achievement consists in the genetic modifications of the MSOD-B cells by CRISPR-Cas9, in order to generate custom ossicles. This has been tested for the silencing of VEGF and RUNX2, and is further exploited to test the impact of additional genes on ossicle formation and hematopoietic development. A manuscript is being compiled and will be submitted soon.
Last, we have work on the development of a product defined as OssiGel. This was further supported by the ERC proof-of-concept grant received in 2022. The OssiGel is being exploited in the ERC project for the formation of autologous ossicles: with the human niche and engrafted leukemic cells from the same donor. This has been a challenge so far, since the formation of autologous ossicles was poorly reproducible. Using the OssiGel technology, we can achieve a reproducible formation of patient ossicles. We have compiled extensive data on this, presented at various international conferences. We are willing to submit a manuscript in 2024. In parallel, we are willing to develop a start-up company for the commercialization of OssiGel.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

hOssicle is expected lead to fundamental and translational outcomes. Fundamentally, the approach ambitions to address long-lasting questions in the field such as the localization of HSCs, the functional differences between osteoblastic versus vascular niches, and the role of the niche environment during leukemic development. Translationally, the development of robust ossicle technologies will allow the modeling of leukemia, ideally in a personalized manner. By forming patient ossicles, we could test a variety of drugs and refine their clinical selection at diagnostic or relapse. Beyond leukemia, such models can also be applied to solid cancers metastasizing to bones.

Engineering of human ossicles