Simple Summary
Neurofibromatosis type 1 is a common genetic disorder caused by loss-of-function mutations in the NF1 gene. NF1 deficiency drives constitutive RAS signaling and manifests a broad spectrum, from pigmentary changes to malignant peripheral nerve sheath tumors. Currently, the only approved therapy is MEK inhibition, which targets a limited subset of phenotypes and is not curative. In this review, we summarize NF1-driven signaling and emerging therapies, including AAV-based gene therapy, oHSV therapy, CAR-T cell therapy, and other molecular-targeted approaches. We emphasize recent progress in AAV-mediated delivery of the GAP-related domain using engineered capsids with Schwann-cell tropism. We discuss the advantages, the problems these strategies address, and their limitations. Understanding these evolving therapies could guide the development of improved therapeutic methods, enable rational combinations, and ultimately advance toward more comprehensive disease control.
Abstract
Mutations in the NF1 gene cause Neurofibromatosis Type 1 (NF1), one of the most common genetic disorders. This gene encodes neurofibromin, a member of the GTPase-activating protein (GAP) family that functions as a negative regulator of RAS signaling. Loss of NF1 function leads to persistent RAS activation and promotes tumor growth. The clinical manifestations of NF1 mainly include pigmentary changes, benign and malignant peripheral nerve sheath tumors, as well as gliomas affecting the central nervous system. Currently, MEK inhibition is the only approved therapy and is primarily effective in controlling plexiform neurofibromas (pNFs). However, more comprehensive treatments are needed to address the full spectrum of NF1 manifestations and malignant transformation. Novel therapeutic strategies, including AAV-based gene therapy aimed at restoring NF1 function, oncolytic herpes simplex virus (oHSV) therapy targeting RAS-dysregulated tumor cells, and chimeric antigen receptor T cell (CAR-T) therapy targeting NF1-associated tumors, are under active investigation. In this review, we explore the genetic mechanisms underlying NF1 and highlight recent advances in therapeutic development with a special focus on AAV-based gene therapies alongside other approaches with recent clinical and translational advancements.
Keywords:
neurofibromatosis type 1 (NF1); neurofibromin; NF1 gene; plexiform neurofibromas (pNFs); malignant peripheral nerve sheath tumors (MPNSTs); MEK inhibitor; AAV-based gene therapy; GAP-related domain (GRD); oncolytic herpes simplex virus (oHSV) therapy; chimeric antigen receptor T cell (CAR-T) therapy