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Combined isolation and stable non-viral transfection of hematopoietic cells- a novel platform technology for ex vivo hematopoietic stem cell gene therapy

Final Report Summary - MAGSELECTOFECTION (Combined isolation and stable non-viral transfection of hematopoietic cells - a novel platform technology for ex vivo hematopoietic stem cell gene therapy)

This project was conceived in early 2004 and was submitted for review in November of that year. By that time, the feasibility of ex vivo gene therapy in humans had been demonstrated with retrovirally transduced hematopoietic stem cells. At the same time, risks associated with the use of retroviral vectors had become apparent. Therefore, this consortium had intended to develop a novel non-viral integrated ex-vivo cell separation / transfection platform, suitable for site-specific genomic integration of transfected nucleic acids into non-coding regions of the host genome. This concept was to be applied to hematopoietic stem cells (HSC) and to be validated with established preclinical models of SCID-X1, a rare hereditary immuno deficiency. The MAGSELECTOFECTION platform technology was to be based on a clinically approved magnetic cell separation technique (MACS technology from project partner Miltenyi Biotec, Germany) combined with magnetically enhanced transfection (Magnetofection1) and on nucleic acid constructs that were to provide site-specific genomic integration.

% The project consortium has succeeded in combining nanomagnetic cell separation in one procedure with the genetic modification of cells, in particular of stem cells. MAGSELECTOFECTION, if carried out according to an optimised protocol, produces a high yield of selected target cells at high purity of which a high percentage is genetically modified. In particular, selected and modified cells display high viability and excellent biological functionality. Hematopoietic and mesenchymal stem cells that have been engineered by MAGSELECTOFECTION retain their pluripotent characteristics and can differentiate into multiple lineages. Magselectofected hematopoietic stem cells can reconstitute the hematopoietic compartment in mouse models. MAGSELECTOFECTION is a platform that comprises a minimum number of handling steps, it is simple to execute, it is efficient and it is amenable to automation. First commercial products for research use were launched in the year 2010. A product for clinical use will be developed depending on demand.

Together with the knowledge about manufacturing suitable magnetic nanoparticles, the knowledge of how to combine magnetic cell separation and nucleic acid delivery is the key knowledge for performing MAGSELECTOFECTION. This knowledge will be published and will also be part of the application notes of commercial MAGSELECTOFECTION kits. The knowledge is protected by patents or patent applications as listed in the table. However, a more essential protection is trade secrets on the manufacturing of magnetic nanoparticles which are in the possession of OZ Biosciences and independently of Miltenyi Biotec. Non-commercial exploitation will be by the scientific community who will use this published knowledge for their research purposes. Commercial exploitation will be by the project partners Miltenyi Biotec and OZ Biosciences. The first product to be launched will be magnetic nanoparticles for MAGSELECTOFECTION together with a protocol for performing MAGSELECTOFECTION. OZ Biosciences and Miltenyi will negotiate an agreement for commercialisation of a complete MAGSELECTOFECTION kit, comprising magnetic cell separation columns and a separator magnet from Miltenyi and magnetic nanoparticles and optionally a nucleic acid from OZ Biosciences. All of this may be suitable for licensing, for example under OEM contracts, if economically meaningful. Market considerations are too early for MAGSELECTOFECTION technology. However, in regenerative medicine alone, MAGSELECTOFECTION meets a billion dollar market. As a truly enabling technology, MAGSELECTOFECTION may be worth several hundred million euros over a product cycle. Many OZ Biosciences products have been launched already. Such products can bring revenues of several hundred thousand euros per year within a few years of market presence if successful in the hands of customers.