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Gene-targeted therapy for neurofibromatosis and schwannomatosis: The path to clinical trials.

  • Staedtke, Verena1
  • Anstett, Kara2
  • Bedwell, David3
  • Giovannini, Marco4
  • Keeling, Kim3
  • Kesterson, Robert5
  • Kim, YooRi6
  • Korf, Bruce7
  • Leier, André7
  • McManus, Miranda L8
  • Sarnoff, Herb9
  • Vitte, Jeremie4
  • Walker, James A10
  • Plotkin, Scott R11
  • Wallis, Deeann7
  • 1 Department of Neurology, Johns Hopkins University, Baltimore, MD, USA.
  • 2 Department of Neurology, NYU Grossman School of Medicine, New York, NY, USA.
  • 3 Department of Biochemistry and Molecular Genetics, University of Alabama at Birmingham, Birmingham, AL, USA.
  • 4 Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA and Jonsson Comprehensive Cancer Center (JCCC), University of California Los Angeles, Los Angeles, CA, USA.
  • 5 Department of Cancer Precision Medicine, Pennington Biomedical Research Center, Baton Rouge, LA, USA.
  • 6 Gilbert Family Foundation, Detroit, MI, USA.
  • 7 Department of Genetics, The University of Alabama at Birmingham, Birmingham, AL, USA.
  • 8 Department of Biology, College of Charleston, Charleston, SC, USA.
  • 9 Infixion Bioscience, Inc., San Diego, CA, USA.
  • 10 Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
  • 11 Department of Neurology and Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
Published Article
Clinical trials (London, England)
Publication Date
Feb 01, 2024
DOI: 10.1177/17407745231207970
PMID: 37937606


Numerous successful gene-targeted therapies are arising for the treatment of a variety of rare diseases. At the same time, current treatment options for neurofibromatosis 1 and schwannomatosis are limited and do not directly address loss of gene/protein function. In addition, treatments have mostly focused on symptomatic tumors, but have failed to address multisystem involvement in these conditions. Gene-targeted therapies hold promise to address these limitations. However, despite intense interest over decades, multiple preclinical and clinical issues need to be resolved before they become a reality. The optimal approaches to gene-, mRNA-, or protein restoration and to delivery to the appropriate cell types remain elusive. Preclinical models that recapitulate manifestations of neurofibromatosis 1 and schwannomatosis need to be refined. The development of validated assays for measuring neurofibromin and merlin activity in animal and human tissues will be critical for early-stage trials, as will the selection of appropriate patients, based on their individual genotypes and risk/benefit balance. Once the safety of gene-targeted therapy for symptomatic tumors has been established, the possibility of addressing a wide range of symptoms, including non-tumor manifestations, should be explored. As preclinical efforts are underway, it will be essential to educate both clinicians and those affected by neurofibromatosis 1/schwannomatosis about the risks and benefits of gene-targeted therapy for these conditions.

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