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

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.
Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: V.S. serves as a scientific advisor for the Gilbert Family Foundation Gene Therapy Initiative. H.S. is Founder/CEO of Infixion Bioscience, an early-stage drug discovery company targeting NF1. R.K. serves as a Scientific Advisor for Infixion Bioscience Inc. (3210 Merryfield Row San Diego, CA 92121). Y.K. serves as scientific officer at the Gilbert Family Foundation and as a member scientific advisory panel of NTAP’s Gene Therapy program. S.R.P. is co-founder of NFlection Therapeutics and NF2 Therapeutics and consults for AstraZeneca, SonalaSense, and Akouos. B.K. is a consultant for GenomeMedical, Recursion, Healx, and Springworks.