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Page 2 of 11 Okaz et al. Rare Dis Orphan Drugs J. 2025;4:24 https://dx.doi.org/10.20517/rdodj.2025.15

encodes neurofibromin, a tumor suppressor protein critical for regulating cell growth and proliferation.
Neurofibromin functions as a GTPase-activating protein (GAP) that reduces Ras signaling by stimulating
[1]
the hydrolysis of active RAS-GTP to inactive RAS-GDP, classifying NF1 as a RASopathy . NF1 affects
approximately 1 in 2,500 to 3,000 individuals worldwide, with an estimated 100,000 affected in the United
States . It can be inherited in an autosomal dominant manner or arise from spontaneous germline
[1,2]
[1]
mutations. The disease exhibits a wide variability in its presentation, even within the same family .
Neurofibromin is ubiquitously expressed, with the highest levels in the central nervous system, particularly
in neurons, glial cells, Schwann cells, and peripheral nerve trunks. Haploinsufficiency of neurofibromin or
its complete loss impacts multiple cellular processes such as receptor-mediated signaling and cell fate
[3]
decisions, which contribute to NF1’s broad and variable phenotypes . NF1-associated tumors can develop
anywhere in the nervous system and range from benign neurofibromas to malignant peripheral nerve
sheath tumors (MPNSTs). Benign cutaneous neurofibromas, often disfiguring, are a hallmark feature of
NF1. Plexiform neurofibromas, present in up to 50% of patients, carry the risk of malignant transformation.
Additionally, 15%-20% of NF1 patients develop optic pathway gliomas, which can impair vision due to
retinal ganglion cell loss. High-grade gliomas, though rare, are a leading cause of NF1-associated mortality.
Complications of NF1 can extend to cardiovascular problems, chronic pain, and learning challenges, with
approximately 50% of patients experiencing cognitive or academic difficulties .
[4]
Addressing NF1’s complexity requires innovative approaches to tackle its genetic and molecular
underpinnings. The Gilbert Family Foundation’s (GFF) Curing NF initiatives reflect this strategy by
supporting the development of cutting-edge technologies and collaborative research in the community of
NF1 researchers to address the disorder’s most pressing challenges. Through these efforts, GFF-funded
researchers aim to better understand the molecular underpinnings of NF1’s diverse manifestations, improve
therapeutic options, and ultimately enhance the quality of life for patients. Launched in 2018, these efforts
focus on advancing gene therapy for all NF1 manifestations, vision restoration for patients with
NF1-associated optic pathway gliomas, and brain tumor treatments for NF1-associated high grade gliomas.
Recently, GFF launched a program to support the development of next-generation preclinical models of
NF1 to improve understanding of NF1 pathogenesis and facilitate clinical translation of potential therapies.

THE GILBERT FAMILY FOUNDATION’S GENE THERAPY INITIATIVE: A THREE-
COMPONENT APPROACH
The gene therapy initiative (GTI) research consortium efforts are primarily at the preclinical proof-of-
concept stage and are designed to lay a strong foundation for future breakthroughs in NF1 treatment. As
illustrated in Figure 1 and elaborated below, the GTI long-term strategy has three interconnected
components that synergistically reinforce each other to support: (1) discovery research to fill critical
knowledge gaps in NF1-associated biochemical pathways, pathology, and other unmet research needs, (2)
enabling technology and infrastructure, such as assays, delivery systems, and preclinical models to advance
NF1 research, and (3) advancing gene, cell, and other novel therapeutic approaches to treat NF1.

Discovery research to fill critical knowledge gaps in NF1 pathways, pathology, and other unmet
needs within the NF1 research field
Advancing our understanding of NF1 at both molecular and clinical levels
Advancing our understanding of NF1 at both the molecular and clinical levels is critical for developing
therapeutic interventions to prevent or treat various clinical manifestations resulting from altered cell fates
and cell states caused by pathological reduction in neurofibromin levels in various cell lineages. This
includes enhancing our knowledge of cell- and tissue-specific intracellular pathways dysregulated in NF1,