Genetically Manipulated Cornea for Transplantation
Keywords
Ex vivo corneal graft, MHC class I & II silencing, CIITA inhibition, β2-microglobulin, allogeneic transplantation
Invention Novelty
The invention discloses ex vivo genetically modified corneas in which shRNA/siRNA constructs are used to selectively reduce MHC class II expression across HLA-DR, -DQ and -DP and optionally suppress MHC class I via β2-microglobulin or CIITA targeting. Modification is performed directly on the isolated, living graft in serum-free organ or cell culture using lentiviral vectors whilst preserving tissue architecture. Unlike prior approaches, this method aims for broad simultaneous silencing of multiple HLA class II transcripts and optional class I suppression to prevent immune reactions even in sensitized recipients.
Value Proposition
The technology addresses high-risk patients with neovascularization, ocular inflammation, or prior grafts who often fail standard treatment. Pre-treated, less immunogenic corneas could improve graft survival, reduce systemic immunosuppression and avoid repeated surgeries as a therapeutic benefit.
Corneas transduced with shRNA expression cassettes specific for silencing β2-microglobulin (shβ2m) or alpha-chain of H2E (shH2Ea) or CIITA (shCIITA). Results are compared to non-transduced corneas and corneas transduced with control shRNA (shNS) and show an effective silencing for all three targets. (source: EP 3669900B1)
Technology Description
A viable donor cornea is maintained in serum-free organ culture and briefly exposed to lentiviral particles carrying expression cassettes for shRNA/siRNA. Targets include alpha and/or beta chains of HLA-DR/DQ/DP, CIITA and optionally β2-microglobulin. Results from preclinical studies demonstrated preserved histology, effective silencing and diminished humoral and cellular alloimmune responses. Therefore, the technology offers a promising approach for pre-treated corneas off the shelf with lower long-term care costs and broader usability of donor tissue for difficult cases.
Commercial Opportunity
In-licensing or developmental cooperation is possible.
Development Status
Preclinical studies in mice confirmed the technical feasibility of the technology.
Patent Situation
European patent (EP 3669900 B1) with priority of 2018 has been granted and validated (DE, FR, GB, CH, IT).
Further Reading
Figueiredo C, Vahlsing S, Valtink M, Boergel M, Engelmann K, Blasczyk R. 2012. Silencing HLA Class I Expression in Human Corneas to Decrease the Risk of Graft Rejection after Keratoplasty. Transplantation Journal. 94. 955. doi: 10.1097/00007890-201211271-01888.
Yu T, Rajendran V, Griffith M, Forrester JV, Kuffová L. 2016. High-risk corneal allografts: A therapeutic challenge. World J Transplant. 24; 6:10-27. doi: 10.5500/wjt.v6.i1.10.
Institute of Origin
