Exploring Nonsense Suppressionas 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, PhDUniversity of Alabama, Birmingham

Bruce Korf, MD, PhDUniversity of Alabama, Brimingham

Mark Suto, PhDSouthern Research

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, PhDDuke University

David V. Schaffer, PhDUniversity of California, Berkeley

David G. Kirsch, MD, PhDDuke University

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, PhDUniversity of Massachusetts

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, PhDUniversity of Alabama, Birmingham

Jiangbing Zhou, PhDYale University

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.

Andr Leier, PhD University of Alabama, Birmingham

Ulrich Muller, PhDUniversity of California, San Diego

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 with inactivated both copies of the NF1 gene will be identified, particularly those for which an FDA-approved drug is already available.

Eric Pasmant, PharmD, PhDUniversity Paris Descartes

Raphal Margueron, PhDInstitut Curie

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, PhDUniversity of Massachusetts

Scot Wolfe, PhDUniversity of Massachusetts

Matthew Gounis, PhDUniversity of Massachusetts

Jonathan Watts, PhDUniversity of Massachusetts

Xandra Breakefield, PhDMassachusetts General Hospital

Casey Maguire, PhDMassachusetts General Hospital

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, PhDUniversity of Alabama, Birmingham

Linda Popplewell, PhDRoyal Holloway University of London

Link:
Gene Therapy Initiative - gilbertfamilyfoundation.org

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