NF1 results from mutations or deletion of the neurofibromin 1 (NF1) gene, which encodes a negative regulator of the Ras signal transduction pathway called neurofibromin. To date, drug development has primarily focused on addressing the molecular abnormalities that arise downstream of the NF1 gene mutation/deletion. There are no therapies that address the underlying issue of this genetic disease; present therapies do not cure the disease. Thus the mission of the Gilbert Family Foundation's Gene Therapy Initiative (GTI) is to develop curative therapies that address the underlying genetic abnormalities in NF1 patients. In its first phase, the Gene Therapy Initiative will explore the feasibility of various gene-targeting therapeutic strategies for NF1 as well as novel or enhanced in vivo gene delivery systems. Areas of interest thus include:
  • Gene replacement
  • Gene editing
  • RNA editing
  • Exon skipping
  • Mutation suppression
  • Gene delivery systems
Initial Gene Therapy Initiative awards were announced in December 2018 and the second cycle will be announced in January 2022.

Exploring Nonsense Suppression as a Treatment for NF1

This project aims to find compounds that suppress the effects of nonsense mutations in the NF1 gene, thus restoring neurofibromin protein expression and function in NF1 patients.

David Bedwell, PhD 
University of Alabama, Birmingham

Bruce Korf, MD, PhD
University of Alabama, Birmingham

Mark Suto, PhD
Southern Research

Genome Editing with Engineered Vectors to Correct Neurofibromatosis Type I

This project will resolve two primary challenges applying gene therapy approaches to NF1 by using an innovative strategy to engineer new viruses that targets tumor initiating cells and CRISPR-based genome editing to restore the mutated NF1 gene. Using a unique team with complimentary expertise, this venture applies some of the most exciting modern biotechnologies to NF1.

Charles Gersbach, PhD
Duke University

David V. Schaffer, PhD
University of California, Berkeley

David G. Kirsch, MD, PhD
Duke University

Ataluren-promoted Therapeutic Nonsense Suppression for Neurofibromatosis

Ataluren is a drug that can suppress protein synthesis termination at premature nonsense codons to produce essential proteins in patients with Duchenne muscular dystrophy. This project aims to evaluate its effect on mouse cells with an NF1 gene that harbors nonsense mutations.

Allan Jacobson, PhD
University of Massachusetts

NF1 Gene Rescue in Translational Animal Models

This project proposes using nanoparticles to deliver 1) key coding regions of NF1 gene (cDNA) that will make neurofibromin protein, and 2) gene-editing regents to directly correct the mutation that causes NF1 in a patient derived NF1 rat model. If successful, the new system will provide essential pre-clinical data and lay the foundation for clinical trials using nanomedicine to treat NF1 disease.

Robert Kesterson, PhD
University of Alabama, Birmingham

Jiangbing Zhou, PhD
Yale University

NF1 RNA Repair Based on Therapeutic Ribozymes

This project will bioengineer trans-acting ribozymes, RNA molecules with catalytic properties similar to protein enzymes, to target faulty transcripts of the NF1 gene that fail to translate functional neurofibromin. NF1 mouse models with patient specific mutations that are amenable to ribozyme-mediated correction will be developed for subsequent animal studies.

André Leier, PhD
University of Alabama, Birmingham

Ulrich Muller, PhD
University of California, San Diego

Investigating Synthetic Lethality Associated with NF1 Loss

The mutation of one gene, e.g. NF1, often makes other genes that are not normally required for cell survival vulnerable to inactivation. This project aims to kill cells that have inactivated both copies of the NF1 gene. Using CRISPR/CAS9 technology, genes that become essential for the survival of cells that have two inactivated copies of the NF1 gene will be identified, particularly those for which an FDA-approved drug is already available.

Eric Pasmant, PharmD, PhD
University Paris Descartes

Raphaël Margueron, PhD
Institut Curie

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

This project seeks to develop two new NF1 drug candidates by developing and characterizing multiple potential therapeutics in parallel within fourteen research laboratories. AAV vectors for delivery and zinc finger protein and antisense oligonucleotides to upregulate NF1 expression will also be used when evaluating the efficacy of different therapeutic modalities.

Miguel Sena-Esteves, PhD
University of Massachusetts

Scot Wolfe, PhD
University of Massachusetts

Matthew Gounis, PhD
University of Massachusetts

Jonathan Watts, PhD
University of Massachusetts

Xandra Breakefield, PhD
Massachusetts General Hospital

Casey Maguire, PhD
Massachusetts General Hospital

Exon Skipping to Treat Neurofibromatosis Type 1 (NF1) Mutations

Antisense directed gene therapy, or more specifically exon skipping, causes cells to “skip” over faulty pieces of the genetic code, leading to a truncated, but still functional, protein. This project aims to identify exons within the NF1 gene that may be skipped while still maintaining gene function and then develop antisense oligonucleotides to enable modulation of expression.

Deeann Wallis, PhD
University of Alabama, Birmingham

Linda Popplewell, PhD
Royal Holloway University of London

Development of Mutation Suppression Therapy in a Swine Model of NF1

This project aims to investigate the potential of nonsense mutation suppression therapies for NF1 patients using a newly developed swine model. The NF1 pig model can be used to establish the ability of these novel therapies to both eradicate the underlying genetic abnormality and cure existing manifestations of the condition.

Adrienne Watson, PhD
Recombinetics, Inc

David Largaespada, PhD
University of Minnesota

GTI Advisory Board

Barry Byrne, MD, PhD
University of Florida

Leah Byrne, PhD
University of Pittsburgh School of Medicine

Jeffrey Chamberlain, PhD
University of Washington

Manuela Corti, PhD
University of Florida

Kleopas Kleopa, MD
Cyrus Institute of Neurology and Genetics

Verena Staedtke, MD, PhD
Johns Hopkins University School of Medicine


Please email direct inquires to YooRi Kim.