NF1 Gene Rescue in Translational Animal Models

The goal of this project is to assess gene replacement and gene-editing strategies to restore neurofibromin activity in genetically engineered animals harboring NF1 patient specific mutations. In this Phase B project, we build upon our successes to use nanoparticles to deliver a full length NF1 genetic construct. Specifically, we have created a human NF1 mini-gene harboring a HiBiT tag at the carboxy terminus that will be used to monitor transgene expression and biodistribution, as well as for pre-clinical studies in three NF1 relevant animal models; two mouse models (Dhh-cre plexiform spinal tumors and GFAP:cre optic gliomas) as well as in a rat breast cancer model for which we have strong preliminary data showing tumor shrinkage when using nanoparticles to deliver a full-length mouse NF1 cDNA. We are also continuing to develop nanoparticles to deliver CRISPR/Cas9 gene editing reagents in the same three animal models so that single dosing gene correction may be possible to correct the patient nonsense mutation in mice or the patient missense mutation in rats. If successful, the new systems will provide essential pre-clinical data and lay the foundation for clinical trials using nanomedicine to treat NF1 disease.