Title : Gene therapy in pediatric neurosurgery: Delivery strategy and the translational path toward hypothalamic hamartoma
Abstract:
Gene therapy is reshaping the treatment of pediatric neurological disease, offering durable, non-destructive correction of conditions long considered untreatable. This lecture reviews the spectrum of intracerebral gene therapy strategies—gene addition, modification, deletion, and regulation—and positions pediatric neurosurgery as central to their safe and effective delivery. The adeno-associated virus (AAV) remains the dominant vector for central nervous system applications, yet its limited cargo capacity, species-dependent tropism, and modest transduction efficiency in human tissue constrain translation. Equally decisive is the route of delivery: convection-enhanced delivery (CED), intraventricular infusion, and intrathecal administration, along with adjuncts of focused-ultrasound blood–brain-barrier opening each present distinct trade-offs in efficiency, invasiveness, and off-target risk.
Clinical precedent—from the early Canavan and Batten disease trials to the 2024 FDA approval of eladocagene exuparvovec (Kebilidi) for aromatic L-amino acid decarboxylase (AADC) deficiency, the first gene therapy delivered directly into the human brain—demonstrates both the promise and the surgical demands of the field. Pediatric delivery introduces distinct challenges, including skull fragility, cranial fixation risk, and the need for floating-frame, skull-mounted, and robotic stereotactic platforms, alongside vector-related toxicities such as insertional mutagenesis, immune and transgene-mediated adverse events, and dorsal root ganglion toxicity.
The lecture culminates in a translational framework for hypothalamic hamartoma (HH), an intrinsically epileptogenic lesion for which intralesional, physiologically based gene therapy—such as activity-dependent hyperpolarizing constructs—may offer a non-destructive alternative to ablation. Realizing this potential will require studies on living human HH tissue, networked biopsy and tissue-banking protocols, advances in cell-type-specific tropism, and early, sustained collaboration between neurosurgeons and biologics developers. Early neurosurgical engagement in delivery design is identified as a critical determinant of safe and effective therapy.
Keywords: Gene therapy; pediatric neurosurgery; adeno-associated virus (AAV); convection-enhanced delivery; hypothalamic hamartoma; AADC deficiency; stereotactic delivery; epilepsy.
