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Page 6 of 11 Okaz et al. Rare Dis Orphan Drugs J. 2025;4:24 https://dx.doi.org/10.20517/rdodj.2025.15

and 2). If delivery and safety challenges are also overcome, gene therapies could offer a one-time or at least a
more durable, disease-modifying intervention with broader impact and fewer side effects. MEK inhibitors
have validated RAS-MAPK targeting in NF1 but deliver partial and non-curative benefits. While MEK
inhibitors represent an important clinical advance, their limitations highlight the pressing need for therapies
that address the underlying biology of NF1 rather than primarily mitigating downstream consequences. The
FDA-approved MEK inhibitor, selumetinib, has shown effectiveness in a subset of patients; however, there
is heterogeneity in patient response, the therapy can cause significant side effects, and plexiform
[25]
neurofibromas do not completely disappear . Recent clinical trials confirm that MEK inhibitors can shrink
plexiform neurofibromas, but the responses are incomplete, variable and come at the cost of chronic
toxicity [26-29] .

Within this framework, gene therapy strategies are being designed to tackle the root cause of NF1 and halt
disease progression by compensating for the loss or dysfunction of neurofibromin through gene
replacement via the cellular introduction of genetic material encoding the NF1 gene either in full or in part,
mutational targeting by editing NF1 pathogenic variants or by editing, modulating, or overriding
pathogenic NF1 mutations at the mRNA level, and enhancing the neurofibromin levels produced by the
remaining wild-type NF1 allele in haploinsufficient cells. For a detailed description of the Gilbert Family
Foundation’s Gene Therapy Initiative project portfolio, readers can visit the GFF Curing NF website (https:/
/gilbertfamilyfoundation.org/curing-neurofibromatosis/). Next, we highlight some such promising gene
therapy tools and approaches that are currently under development.

EV-based nanocarriers for NF1 and other novel gene delivery technologies
Gene therapies have been identified as a promising avenue for the treatment of NF1 [3,30] . However, proper
deployment of such therapies remains a significant challenge due to difficulties in delivering large genes like
NF1 and targeting cells of interest, such as Schwann cells, where restoration of neurofibromin can have a
therapeutic effect in certain manifestations. At the technology development level, advancing innovative and
disruptive viral and non-viral gene delivery modalities, along with other gene therapy technologies, would
be important. These approaches not only serve as delivery vehicles for NF1 therapeutic payloads but also
serve as important tools that can be used in exploring NF1 biology, interrogating the NF1 pathway, and
driving the discovery of novel NF1 therapeutic strategies.

Gene delivery using adeno-associated viruses (AAVs) has shown promise in various genetic disorders.
However, its application faces several limitations . AAVs have a limited packaging capacity (approximately
[31]
4.7 kb), restricting their ability to deliver large genes like NF1. Furthermore, pre-existing immunity against
AAVs can reduce transduction efficiency, as individuals may have neutralizing antibodies due to prior
exposure. Additionally, long-term gene expression may diminish in dividing cells, necessitating repeated
administration, which poses further immunological challenges. These limitations highlight the need for
alternative or enhanced delivery systems to effectively target NF1.

Extracellular Vesicles (EVs) are cell-derived natural carriers that play a critical role in mediating
intercellular communication by transferring various biomolecules, such as proteins, DNA, and RNA, under
[32]
both healthy and pathological conditions . Engineered extracellular vesicles (eEVs) represent a promising
novel delivery platform that can carry therapeutic payloads [33,34] . Recent studies provide preliminary
evidence that EVs can be engineered to carry NF1-relevant therapeutics, including mRNA, plasmid DNA,
and protein content, and can effectively deliver these cargos to recipient cells, resulting in the expression of
non-mutated NF1 [35,36] . Compared to viral vectors, eEVs can potentially overcome key limitations, such as
capsid size constraints and redosing challenges, while also improving upon the low transfection efficiencies