Most therapeutic approaches for NF1 have focused on blocking a specific cell signaling pathway, called Ras/MAPK, which is hyperactive in cells that have lost NF1 function due to gene mutation. This approach has yielded exciting advances, including the development of MEK inhibitor drugs such as selumetinib for the treatment of plexiform neurofibromas. However, MEK inhibitor medications are not effective for all plexiform neurofibromas, and none of the tumors completely disappears on treatment.

While the development of mechanism-based therapies is critically important, the UAB NF Research Program is focused on another promising area of NF research – the development of genome-guided therapeutics with the goal of restoring function to the mutated NF1 gene or gene product. We have been pioneers in this effort for NF1 and have developed resources to enable this research through many funding resources, including the Gilbert Family Foundation (Gilbert Family FoundationGene Therapy Initiative – Gilbert Family Foundation).

Nonsense Suppression Therapies

This project focuses on the identification of drug compounds capable of reading through a type of truncating mutation called a premature stop, or nonsense mutation, which affects about 20% of individuals with NF1. This type of mutation inserts a signal that tells the protein production machinery in the cell to stop production of neurofibromin before the complete protein is made, resulting in a shortened, nonfunctioning protein, or in most cases, complete absence of protein production from the mutated copy of the gene.

Drug compounds have been identified that have shown promise in overcoming the effects of premature stop mutations. The concept for this type of research was developed by David Bedwell, Ph.D., chair of the UAB Department of Biochemistry and Molecular Genetics, who serves as the principal investigator for the project. The focus is to identify and test drug compounds capable of reading through premature stop mutations in the NF1 gene, with the goal of allowing cells to produce a full-length, functional neurofibromin protein.

Genome Editing and Gene Replacement for NF1

Conducted by UAB investigator Bob Kesterson, Ph.D., in conjunction with researchers at Yale University, this project utilizes two approaches to restore gene function. First, CRISPR/Cas9 gene editing technologies are used to correct mutant to NF1 genes at the DNA level in animals that have been engineered to carry various NF1 mutations found in human patients.  In the second approach, the team delivers a full-length copy of the NF1 gene directly to animals, which then synthesize the NF1 protein in cells that lack the neurofibromin protein. The preclinical data generated could serve as the foundation for clinical trials of genomic therapeutics that utilize gene editing and/or gene replacement to correct NF1.

Exon Skipping for NF1

This project, conducted by UAB investigator Deeann Wallis, Ph.D., in conjunction with researchers from the Royal Holloway University of London, focuses on correcting NF mutations in model systems using a technique called exon skipping. This process causes cells to skip over mutations in the genetic code while still producing a functional protein. A gene is encoded in segments, called exons, which code for the amino acids of a protein, separated by introns, which are intervening sequences. The purpose of this project is to identify exons within the NF1 gene mutation that can be skipped while still maintaining function of the gene, allowing these mutations to be bypassed.

Engineered Trans-Splicing Ribozymes for (Pre-)mRNA Repair

Led by UAB investigator André Leier, Ph.D., in conjunction with a researcher from the University of California, San Diego, this research initiative is developing a ribozyme-based NF1 messenger RNA (mRNA) repair therapy and testing it in NF1 mouse models with patient-specific mutations. Ribozymes are RNA molecules with catalytic properties, similar to protein enzymes. The ribozymes have been designed to specifically target and repair faulty NF1 mRNA, i.e., transcripts of the faulty NF1 gene, by removing the end of the mRNA that contains the pathogenic mutation and replacing it with its correct version. The hope is that sufficient transcripts of the faulty NF1 gene can be repaired that will translate into fully functional proteins that provide a therapeutic effect.