Cells derived from suitable donor stem cells that can do the work defective insulin-producing cells can no longer do are the central focus of a European cell therapy project involving Reutlingen-based Cellendes GmbH as one of the partners. Cellendes develops a biomaterial that facilitates the mass production of cells and could potentially be approved for therapeutic use in humans.
Between five and ten percent of all diabetes patients suffer from type 1 diabetes, formerly also known as juvenile diabetes. Type 1 diabetes is the result of the autoimmune destruction of the insulin-producing beta cells in the pancreas. Little or no insulin is thus produced. Beta cells cannot, however, be regenerated in vivo. As children are frequently affected by type 1 diabetes and a causal treatment is not yet available, researchers around the world are working intensively on developing new forms of treatment. Transplantation of the pancreas or insulin-producing islets of Langerhans are the only two effective forms of treatment available. However, it goes without saying that healthy donor organs are required, but in many cases not available.
Thanks to stem cell technology, there is now another option for treating the condition. This involves using a small number of pancreatic stem cells that come from a suitable donor, which then produce a large number of beta cells for transplantation. A new EU-funded research consortium (LSFM4LIFE) was set up in early 2016 with the aim of turning the idea into a treatment regimen. The consortium involves Reutlingen-based Cellendes GmbH, a company that specialises in developing and producing custom hydrogels for cell cultures. “The discovery of adult stem cells in the pancreas was groundbreaking. Now we want to multiply and develop these stem cells into beta cells under GMP conditions. We use a standardised method that complies with all regulatory requirements,” says Dr. Brigitte Angres who founded and manages Cellendes GmbH with her colleague Dr. Helmut Wurst.
Whether or not the cells can be used for human therapy depends on whether regulatory approval can be obtained. The method itself works quite well. Stem cells are cultured and, when transplanted into animal models, develop into insulin-producing cells. In culture, the cells form structures that mimic the situation in the tissue of origin. “More or less round, hollow epithelial-like pancreas organoids develop. They therefore correspond to the environment of the pancreatic duct from where the cells were removed,” said Angres. Prior to developing this method, the researchers used a matrix consisting of purified mouse tumour tissue. This tissue naturally contains extracellular matrix components that promote cell growth.
This kind of matrix is ideal for cultures used for research purposes, but unfortunately cannot be used for treating humans. “It takes far too long to characterise the carrier substance and obtain regulatory approval for therapeutic application. Matrixes like these are associated with several problems. On the one hand, they are animal-derived, and on the other, they contain far too many unknown components, including growth factors of which nothing is yet known,” said Angres. Cellendes, a company with a great deal of expertise in the delivery of specialised solutions, has therefore decided to develop artificial hydrogels with a defined composition of biologically inert polymers and biopolyers. Cellendes’ toolbox enables hydrogels to be manufactured according to certain applications and functional needs. As far as this project is concerned, the matrix is modified biomimetically in a way that enables the cells to obtain growth-promoting biochemical signals.
“We are looking to incorporate short peptides from extracellular matrix proteins into the hydrogels. These peptides have an amino acid motif to which cell surface receptors can bind,” says Angres. This binding triggers intracellular signalling pathways that lead to the reorganisation of the cytoskeleton and growth of the cells. In the subproject Cellendes is involved in, the company’s team is attempting to identify the best hydrogel composition for optimal growth conditions. As the ultimate goal is mass production of cells, Cellendes is faced with another challenge: as the cells multiply and cell numbers increase, space becomes scarce and the cells need to be transferred into new culture vessels. This means that the organoids have to be removed from the gel, broken up and transferred to a new matrix. Cellendes has a variety of enzymatic and chemical methods to achieve this and is now concentrating on identifying the best method.
The multinational research network is being coordinated by a group of researchers at the University of Frankfurt. This particular group is working on the optimisation of light sheet microscopy methods to enable the accurate characterisation of Cellendes’ matrix and the cells it contains. The Frankfurt team is also working with the Gordon Institute, one of the project partners at Cambridge University, on the analysis of biomarkers. Clinical partners from Cambridge University provide the donor tissue and carry out studies with mouse models. The project also involves a group of clinicians from Milan, whose role will be to contribute everything needed for testing the method in a clinical study with humans. Last but not least, the project also involves industrial partners from the Netherlands, Switzerland and France. (Detailed information and project updates can be accessed through the LSFM4LIFE link listed under “Further information”). The project is funded by the EU with 5.1 million euros over a period of four years.
“We believe that the project opens up a great opportunity for the effective treatment of type 1 diabetes. However, it is too early to say whether a complete cure will be possible or not. We hope that implanting cells will counteract at least some of the insulin shortage associated with the condition,” says Angres who is also pleased with the benefits her company derives from the project. “The project is an excellent opportunity for us to further develop the hydrogel system. We would like to also find ways to establish cultures with other stem cells and organoids. A key culture would be a matrix for intestinal organoids that is also suitable for high-throughput drug screening.”