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used in clinical treatments for other pediatric rare diseases, including rare and ultra-rare neurological
diseases [44,45] . Notably, it has been applied in DMD through the development of exon-skipping therapies
aimed at restoring the reading frame of the dystrophin gene. Recent research identified NF1 exons 17 and
52 as viable exon skipping targets, as their exclusion does not compromise neurofibromin function,
preserving neurofibromin expression and GAP-related domain (GRD) activity, making them promising
therapeutic targets [46,47] .

Further research is needed to optimize nonsense suppression and exon-skipping approaches by testing their
efficacy in NF1 patient-derived preclinical models to identify the specific NF1 mutations and the clinical
manifestation contexts where such therapeutic approaches are likely to be effective.

Rescuing haploinsufficiency by enhancing neurofibromin levels produced by the remaining wild-type NF1 allele
Learning disabilities and behavioral disorders such as attention deficit disorder occur in a significant
percentage of children with NF1 . These challenges are associated with mutations in one of the two copies
[48]
[49]
of the NF1 gene, leading to reduced levels of neurofibromin . Studies in NF1 mouse models have revealed
that these animals develop learning and behavioral problems similar to those observed in humans and thus
provide a valuable resource to study the disease and develop new and improved treatment strategies. A
novel and innovative approach toward treating learning and behavioral deficits in NF1 relies on boosting
levels of the neurofibromin protein within the brain by preventing neurofibromin degradation. Recent work
uncovered a new and important mechanism by which neurofibromin levels are regulated within the cell by
interacting with FBXW11, an F-box E3 substrate adaptor protein that, notably, also regulates the
phosphorylation-dependent ubiquitination and degradation of key factors associated with tumor growth
and aggressiveness . Disrupting FBXW11-mediated degradation of NF1 through genetic disruption of
[50]
FBXW11 can restore neurofibromin protein levels within key brain areas responsible for learning and
behavioral disorders associated with NF1 . There is potential for this work to provide a strong foundation
[50]
to advance new gene and small molecule-based therapies toward clinical trials for the treatment of learning
disabilities and behavioral disorders in NF1.

CLOSING REMARKS
Advancing gene therapy for NF1 faces numerous complications such as delivery challenges,
immunogenicity, and manufacturing hurdles [51,52] . Gene therapy for NF1 holds immense promise, but
realizing its full potential demands more than technological innovation. It requires a concerted effort to
address persistent foundational gaps in the field. These include deepening our understanding of NF1 at the
cellular and molecular levels, including how neurofibromin deficiency alters developmental trajectories, cell
fate decisions, and tumor-immune microenvironment interactions, to identify the optimal timing and
cellular context for intervention and to improve patient stratification. It also requires developing sensitive
and scalable assays to quantify neurofibromin restoration and generating reliable preclinical models that
reflect NF1’s heterogeneity and pathophysiology. The Gilbert Family Foundation’s GTI takes a strategic,
integrated approach to overcome these obstacles through its three-pronged strategy supporting discovery
research, enabling infrastructure, and advancing therapeutic development, including gene therapy,
neurofibromin upregulation, and immune-modulatory approaches. These components are not isolated but
are mutually reinforcing drivers that generate critical feedback to inform and accelerate progress across the
broader therapeutic development ecosystem. By confronting these foundational and translational barriers
head-on, the field can transition from proof-of-concept to clinical impact, ultimately transforming NF1 care
through durable, disease-modifying gene therapies. Whether the future of NF1 gene therapy is bright or
bleak depends on how the field embraces and acts to fulfill these prerequisites.