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Corline Heparin Technology - Enabling Regenerative Medicine

Final Report Summary - CORLINE (Corline Heparin Technology - Enabling Regenerative Medicine)

Executive Summary:
The Regenerative Medicine (RM) industry is looking towards launching ground-breaking therapies in many areas. However, innate immunity and overall biological compatibility of grafts (implanted cells and tissue) is still a huge problem, maybe the main hurdle for many therapies today. We see poor cell mass survival at transplantation of e.g. insulin producing cells and liver cells, we see clotting and massive inflammation reactions when decellularized tissue is being introduced in vascular surgery and soft tissue repair.
Conventionally, trying to overcome problems with immunity and inflammation reactions, medicine has tended towards systemic treatments, e.g. giving the patients immunosuppressive or anti-clotting drugs. This treatment strategy is not without risk for the patients and at the same time it seldom offers the local protection needed for the transplanted graft. Graft failure is often the result.
In this landscape, Corline has a truly unique approach to solving these problems. By attaching a coating of heparin (the CHS) directly to the cell-surface, Corline offers local protection without systemic side-effects. It has also been shown that this concept has a broad applicability within Regenerative Medicine, that it can be used on many cell and tissue systems, and that it has many established and potential functions and possible new routes of developments.

Project Context and Objectives:
The overall objective of this project is, for the benefit of the participating SMEs and for the European Regenerative Medicine industry, to advance the use of the CHS technology within multiple areas of application together with the participating SMEs, from the current evaluation phases through pre-clinical studies to a situation where clinical studies are initiated and conducted, and products launched on the market. In parallel, the already approved clinical study within Diabetes Type-1 shall be concluded and result in that Corline’s product is approved to be a part of an ATMP in clinical therapy.
The means for reaching the project objectives is to purchase a substantial amount of outsourced advanced scientific work from European RTDs working in the RM area.

The scientific objective of this project is twofold:
1. to clinically test and show that CHS can be used to protect donated human insulin producing cells that are transplanted to severe cases of Diabetes Type 1 patients, and
2. to broaden the application of the technology and show that the CHS technology can function as a protective and revascularization promoting technology for other Regenerative Medicine areas. The goal is to show in suitable animal models CHS’s further applicability to Liver Cell therapy, Xeno Transplantation of Islet of Langerhans and to Tissue Engineering
In addition to the detailed scientific objective, this project has a specific technological objective.
The technological objective of this project is to, in partnerships with the participating SMEs, improve European top grade clinical Regenerative Medicine products by combining them with the CHS technology, transferring the application knowledge and integrating the CHS technology into the partners’ cell and tissue production processes, and to set up a reliable sourcing chain with supply and production of reagents and tissue products to end-user.

Project Results:

•Received an updated clinical trial approval under new regulatory framework (as ATMP) based on new in vivo data produced during the project.
•Optimized cell heparinisation process to fit a GMP classified cell manufacturing facility. New process was validated in vivo in rats during project
•Developed QC methods and release criteria for a finished ATMP product
•New production facility and logistics set-up developed together with Karolinska, and prepared/tested to serve as ATMP manufacturer for the clinical trial

WP1 faced a situation of not having reached the primary goal of WP1, the recruitment of patients toour clinical study. However, much work has been done and many important results have been achieved that significantly have increased the probability of Corline starting its clinical study in the very near future.

•Proof of concept in vivo that CHS coated fresh liver cells has 100 % better engraftment and produce 2 times the amount of human albumin in a mouse model
•Successful technology transfer of CHS coating protocol/technology to Cytonet’s US manufacturing facility

WP2 has been able to show proof of concept for coated liver cells in vivo. In order to move to further towards commercialization, the product needs to go through efficacy and dosing/safety studies. The main purpose of the dissemination activities following on the project will be to attract an industrial partner interested in financing and running such studies.

•successful tech transfer of the Corline CHS-coating technology to the BetaGraft production set-up.

In comparison with effective non-coated BetaGraft transplantation in mouse models, we did not find clear benefits of the CHS-coated versions of BetaGraft in terms of grafting, immune protection, transplant efficiency or insulin-secretion in our in vivo animal models.
We may in the future study effects of the coating on durability of capsules, storage and handling stability or possible other attributes.

•acellular bovine arteries, coated or uncoated with the CHS, have shown potential in vivo as an arteriovenous access graft.

This initial proof of concept animal study offers good pilot data in support of progressing to a more comprehensive pre-clinical evaluation study.

Potential Impact:
As a result of the project, CHS coated Islet are now ready to be clinically evaluated as ATMP as soon as Islets will be made available to the project. There is a huge potential impact of such as a study as it will produce the necessary data for further development of Islet transplantation as a viable therapy for severe type 1 diabetes, but also serve as a platform for other cell therapies based on cells such as MSCs, liver cells etceteras.
The proof of concept for coated fresh liver cells that could be shown in the project is a good example of expanding the CHS platform in to other cell therapy areas. If the 100 % increase in effectiveness seen in mice can be translated to a clinical situation those would mean that twice as many patients can be treated by use of the same scarce resource of donated liver tissue.
The development of an arteriovenous graft based on acellular bovine arteries in the project may result in a product that stays patent for much longer or a product that can be used in application currently not treatable (coronary arteries or below the knee). Vascular surgeons are constantly trying to develop solutions to access problems or repair of small diameter vessels. The product developed in the project could well become a solution to a ubiquitous problem in current vascular/coronary/renal surgery.

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