The Children’s Tumor Foundation (CTF) is proud to announce a collaboration between Drs. Helen Morrison and Samantha Ginn, employing the power of recent scientific advances, in particular CRISPR-based gene editing, to attempt to restore physiological NF2 gene function.
This project, currently underway at the Leibniz Institute on Aging in Germany and the Children’s Medical Research Institute in Australia, addresses the development of peripheral nerve sheath tumors, including schwannomas and related tumors. These tumors arise from mutations in the NF2 gene, which encodes the tumor-suppressing protein Merlin. When the NF2 gene is mutated in Schwann cells, Merlin production is inefficient, leading to tumor formation. This research aims to develop a therapeutic approach using advanced genome editing technology to address this loss of Merlin function.
This collaboration leverages Prof. Helen Morrison’s expertise in NF2 tumor biology and Dr. Samantha Ginn’s advanced genome editing capabilities to develop a therapeutic strategy for NF2-SWN patients.
Principal Investigators
Prof. Helen Morrison, Leibniz Institute on Aging, Germany
Prof. Morrison’s laboratory has established crucial NF2-dependent schwannoma research capabilities, including a highly relevant and innovative mouse model in which schwannoma formation is induced upon wounding the mouse tail (“nerve crush” model). This model has provided critical insights into tumor formation mechanisms.
Dr. Samantha Ginn, Children’s Medical Research Institute, Australia
Dr. Ginn brings expertise in AAV-based CRISPR-Cas9 genome editing, particularly in treating liver pathologies. Her laboratory is well-equipped to establish similar methodologies for NF2-dependent schwannomas, complementing Prof. Morrison’s tumor biology expertise.
Research Objectives
This project’s main objective is to develop a genome editing strategy to restore physiological levels of Merlin in human Schwann cells.
Another objective of this study is to develop a PDX (Patient Derived Xenograft) model in which a human tumor is implanted into mice. This model will allow the in vivo testing of potential therapies being developed under the project, both in the nerve crush model described above and in a model where human tumor cells are being treated.
Technical Approach
This project uses an innovative gene therapy strategy to address the core defect in the NF2 gene. The approach combines two key technologies: a specialized delivery system (AAV vectors) engineered to target Schwann cells and a precise genetic editing tool (CRISPR-Cas9) that aims at restoring normal NF2 gene function in these cells. This will allow the research team to selectively correct the gene defect in Schwann cells to maximize therapeutic benefit while minimizing safety concerns. This strategy is significant because it targets the fundamental cause of NF2-related schwannomatosis, with the potential to both treat existing tumors and prevent new tumor formation.
The researchers aim to first identify suitable AAV vectors from a pool of 30 preselected candidates and test the ability of these vectors for their efficiency in targeting human Schwann cells before testing these in vivo in the nerve crush model.
In parallel to this work, the PDX model will be developed. If successful, it will allow the in vivo testing of the potential therapies in a closer-to-human setting, thus minimizing the risk of failure in future human trials.
Anticipated Outcomes
The research combines complementary expertise to develop a potential therapeutic approach for NF2-SWN. Success in this project would provide:
- Validation of an AAV-based genome editing strategy for NF2-SWN treatment
- A new PDX model
- Foundational work for treating related nerve sheath tumors
Impact
The funding of this project is an investment in the search for cutting-edge therapeutic technology that could fundamentally change how NF2-SWN is treated. By targeting the root cause of tumor formation – the loss of function of the critical Merlin protein – this work has the potential to prevent tumor development and potentially treat existing tumors. This represents a significant advancement beyond current treatment options, offering hope for more effective, targeted therapy for NF2-SWN patients.
Read our 2021 interview with Dr. Ginn here.
Learn more about NF2-related schwannomatosis here.
