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Lightner. Rare Dis Orphan Drugs J. 2026;5:1 Page 5 of 9

Other tyrosine kinase inhibitors are being investigated through open clinical trials, including crizotinib
(NCT04283669). Lapatinib, a tyrosine kinase inhibitor of EGFR, demonstrated an objective response in 4 of
17 progressive vestibular schwannomas; however, erlotinib was not effective in 11 patients [47,48] . Due to
activation of the AKT/PI3K pathway, histone deacetylase (HDAC) inhibitors are also being investigated,
such as REC-2282 (NCT05130866). The mTOR inhibitors have shown some activity in NF2-related
tumors [49,50] . A trial combining valproic acid (HDAC inhibitor) with bevacizumab and temsirolimus
(NCT01552434) is open and actively recruiting patients.

The MEK enzymes are activated in NF2-related schwannomatosis and NF1. MEK inhibitors have been a
game-changer in NF1-related plexiform neurofibromas and are now approved by the U.S. Food and Drug
Administration (FDA) for children 2 years of age and older (NCT01362803) [51,52] . Treatment with
mirdametinib has also been approved by the FDA for both adults and children [53-55] . NCT03095248
investigated selumetinib in NF2-related tumors; the study is complete, but no results have been posted or
reported.

In preclinical studies, other inhibitors are being investigated, such as pictilisib, a pan-PI3K inhibitor, and
PF-3758309, a PAK inhibitor. Combination treatment demonstrated cell cycle arrest and apoptosis in
merlin-deficient mouse Schwann cells and cell cycle arrest in merlin-deficient human Schwann cells .
[56]

Gene therapy
Finally, gene therapy has changed the course of numerous disease entities, including spinal muscular atrophy
and Duchenne Muscular Dystrophy [57-62] . It is now being investigated in NF1 mouse models and will be the
future of all genetic syndromes, including NF2-related SWN. Prabhakar et al. published encouraging
findings of using adenoviral vectors [adeno-associated virus (AAV1)-constitutive chicken β-actin (CBA)-
FLAG-merlin] to introduce the NF2 into cultured merlin-negative arachnoidal and schwann cells. They
demonstrated the ability of the cells to generate merlin, down-regulate the mammalian target of rapamycin
complex (mTORC), and normalize cell size. The investigators then introduced human schwannomas into
the sciatic nerves of nude mice and monitored tumor growth. They injected the tumors once with the same
AAV1-CBA-FLAG-merlin vector and observed the mice over a 10-week period. Seven of nine tumors
regressed, one remained stable, and one progressed despite treatment. The mice did not appear to experience
treatment-related toxicity. When the tumors were harvested, some atypical cells and areas of hypercellularity
were noted; however, there was clear tumor regression, and Ki67 staining provided further encouraging
results . Others are also studying non-viral vectors, which are more economical and have lower
[63]
immunogenicity and mutagenesis .
[64]
CONCLUSION
In summary, significant progress has been made in understanding NF2-related SWN. The clinical
presentation and genetic findings have been well described, facilitating appropriate diagnosis for clinicians.
The main remaining challenge is differentiating NF2-related SWN from non-NF2-related SWN and
understanding the overlap between them. The modified nomenclature facilitates clearer distinctions between
NF1- and NF2-related SWN. It is clear that surgery is not the mainstay of treatment for schwannomatosis.
Collateral damage to nerve function, along with musculoskeletal and cosmetic complications, frequently
occurs, making systemic treatment essential. Investigators are actively studying sporadic vestibular
schwannomas, NF2-related vestibular schwannomas, and schwannomas at other sites to better understand
tumorigenesis and to expand treatment paradigms. Targeted treatments are now available but remain
limited. An important question is whether targeted therapies in combination would be more effective. Gene
therapy is also being actively investigated. It is only a matter of time before these treatments and approaches
are extended to patients with NF2-related SWN and eventually to those with non-NF2-related SWN. The
natural history of the disease is evolving before our eyes, and patients and their families have reason for
hope.