From hype to hope: foundational requirements for NF1 gene therapy success

Gene therapy for Neurofibromatosis type 1 (NF1), defined as a collection of approaches that restore the quantity and function of neurofibromin, holds promise for treating various NF-associated clinical manifestations by addressing the root cause of the condition. The Gilbert Family Foundation’s Gene Therapy Initiative (GTI) launched one of the first focused research efforts to support a broad array of gene replacement, gene editing, and other strategies aimed at upregulating neurofibromin levels to mitigate symptoms and advance therapies for NF1. Efforts to discover and evaluate novel gene therapies to treat NF1 are hindered by foundational gaps in the field, the absence of quantitative assays, and a lack of robust preclinical models with reliable functional readouts. This perspective begins by shedding light on those key barriers that continue to hinder progress in NF1 gene therapy, outlines some of the strategies being explored to overcome them and offers pointers to additional strategies that merit further exploration. We then highlight several promising gene therapy strategies now in development. Successfully addressing the challenges described earlier is critical to realizing the full potential of these emerging and novel therapeutic approaches, setting the stage for effective and durable NF1 gene therapy interventions.