A Membrane-targeting Construct of NF1 GAP-related Domain (GRD) that Suppresses RAS Activity in NF1-related MPNST, NF1 and other Rasopathies

Unmet Need
Neurofibromatosis type 1 (NF1) is a common genetic disorder that affects approximately 1 in 3,000 individuals worldwide. Patients with NF1 have DNA alterations to the neurofibromin 1 gene which cause RASopathies, a family of diseases caused by altered Ras signaling. RASopathies can include both benign and malignant tumors, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are challenging to treat with even the most aggressive standard of care interventions. There is no cure for MPNSTs and a low chance of long-term survival for MPNST patients. Consequently, there is an urgent need for novel and effective therapies to treat RASopathies, especially NF1-related malignancies.
 
Technology Overview
Hopkins researchers have developed a gene therapy-based method to treat RASopathies, including MPNSTs. This approach utilizes an adeno-associated virus (AAV) delivery system, combined with a NF1 construct that suppresses Ras activation. This AAV vector construct contains the NF1 membrane-targeting GRD (GTPase-activating protein-related domain) fused with an H-Ras C-terminal CAAX motif that suppresses Ras activity. Investigators were able to effectively transduce and suppress Ras signaling in MPNST cell lines and primary Schwann cells. Importantly, adding the membrane-targeting signal increased the potency of the NF1 construct resulting in a significant reduction in cell growth.
 
Stage of Development
In vitro data is available.
 
Publications
Gene Therapy; 24 May 2019
 

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