Table 1.

Recommendations to advance gene therapy in neurodevelopmental psychiatric disorders

Special challenge: Gene dosage •Single-cell expression profiles of genes/isoforms of interest in brain cells throughout development •Development of regulatable vectors for tunable delivery of the therapeutic Special challenge: Delivery to the CNS • Delivery in humans • Development of vector with brain penetrance and cell-type specificity • Comparative analysis of route of administration • Immunosuppressive regimens • Delivery in pre-clinical models • Anatomic limitations • Cell tropism of viral vectors • Pharmacokinetics of oligonucleotides • Toxicity • DRG toxicity • Complement-mediated toxicity • Gene editing/off-target toxicity Special challenge: Timing of intervention and therapeutic windows of opportunity • Centralized resources and access for early genotyping • Newborn screening • Detailed confirmatory testing for enrollment Special challenge: How to measure impact and success • Natural history—an absolute requirement to moving therapy forward • Begin when pre-clinical work starts • Measures that are clinically meaningful to patients • Involve the advocacy community • Consider founder populations for study • Clinical endpoints/biomarkers • Remote/telehealth endpoints • Scoring of videos • Wearables • Sleep monitoring • Seizure monitoring • Other measurable and reproducible markers of disease • Structural MRI • Diffusion MRI • Functional MRI • MRS metabolite quantitation • PET scanning • EEG/ERP • Animal model of efficacy and biomarkers • Gene editing at human locus “humanized mice” • Translational biomarkers • Determining windows of treatment in pre-clinical models