AAV, Zinc Finger Protein and Antisense Oligonucleotide Strategies for Restoration of Neurofibromin Expression

Neurofibromatosis type I (NF1) is a genetic disorder caused by mutations in the neurofibromin gene. Current treatment options are limited and do not address the primary genetic defect associated with this disorder, namely the reduction in levels or complete loss of the neurofibromin protein within affected tissues.

In this project, we seek to develop therapeutics that will directly address this core deficit in NF1 patients. These research efforts will be focused on two principal areas: 1) improved viral delivery systems to deliver therapeutic cargo such as neurofibromin to target cell types (e.g. Schwann cells) and 2) the development of zinc finger proteins and chemically modified oligonucleotides to restore neurofibromin levels in haploinsufficient cells. During the first two years of the project, the efficacy of different therapeutic modalities will be evaluated first in cell culture and then in mouse models of NF1. In year three, we will focus exclusively on advancing the most promising therapeutic strategies through more intense efficacy and safety studies in NF1 mouse models to produce datasets that will be necessary for discussions with the FDA intended to prepare for trials of the drug candidates in patients.