NF1 Gene Rescue in Translational Animal Models

The goal of this project is to test new technologies for correcting NF1 mutations at the genome or DNA level instead of current efforts that are focused largely on regulating targets in the NF1 signaling pathway. We have established a new collaborative team that brings together the expertise of two laboratories, each of which has established critical technologies and reagents on hand that provides a new approach for treating NF1.

The Kesterson lab (UAB) has established several critical reagents for the study of NF1 including a newly created system to study NF1 by having a full-length NF1 cDNA that represents the key “coding” regions of the NF1 gene, which has all the critical information needed to produce the entire neurofibromin protein. His laboratory has also developed the first mice and rats with mutations in their NF1 gene that completely mimic those seen in patients. The Zhou lab (Yale) has developed key technologies based on “nanoparticles” for delivery of large- size DNA like NF1, or for gene-editing reagents known as CRISPR/Cas9 that can correct mutations at the DNA level.

This project conducts needed pre-clinical studies in NF1 relevant animal models to assess the ability to use nanoparticles to 1) deliver the cDNA that will then make neurofibromin protein, and 2) deliver the gene-editing reagents to directly correct the mutation causing NF1. We will also develop rats that carry NF1 patient mutations, and characterize those for tumor formation and cognitive deficits. Rats are well known in the neuroscience field as the preferred species to assess cognitive and behavioral function. Lastly, we will test the ability of the nanoparticles to treat anticipated cognitive and behavioral deficits in the rats with NF1 mutations. If successful, the new systems will provide essential pre-clinical data and lay the foundation for clinical trials using nanomedicine to treat NF1 disease.

Investigators

Robert Kesterson, PhD

University of Alabama, Birmingham

Jiangbing Zhou, PhD

Yale University

Robert Kesterson, PhD

University of Alabama, Birmingham

Jiangbing Zhou, PhD

Yale University

Current Stage

Discovery

Discovery
In Vivo Proof of Concept
IND Enabling
Clinical Trial Phase 1
Clinical Trial Phase 2
Clinical Trial Phase 3