Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)

Spastic paraplegia type 47 (SPG47) is a rare, autosomal recessive, neurogenetic disorder caused by biallelic pathogenic variants in the AP4B1 gene, one of four genes that encode subunits of the adaptor protein complex 4 (AP-4). Together with SPG50, SPG51, and SPG52, SPG47 belongs to the group of AP-4-associated hereditary spastic paraplegias (AP-4-HSP). These disorders are characterized by early-onset global developmental delay, progressive lower limb spasticity, intellectual disability, microcephaly, epilepsy, and motor impairment. The clinical trajectory is typically severe and progressive, with most children ultimately requiring full support for mobility, communication, and daily living activities. There are currently no approved disease-modifying therapies for SPG47. Adaptor protein complexes such as AP-4 are key regulators of vesicle-mediated protein trafficking. While the precise role of AP-4 is not fully understood, research suggests it is involved in the sorting and transport of cargo proteins through the Golgi and plays a critical role in autophagy and neuronal maintenance. Loss of function in any AP-4 subunit results in shared disruption of intracellular trafficking pathways and a common neurological phenotype. This first-in-human, Phase 1/2 open-label clinical trial is designed to evaluate the safety, tolerability, and preliminary efficacy of BFB-101, a gene therapy candidate consisting of an adeno-associated virus serotype 9 (AAV9) vector encoding a codon-optimized full-length human AP4B1 cDNA under control of a ubiquitous promoter. The therapy is delivered as a single dose by intra-cisterna magna injection to target cells in the central nervous system. The primary objective of this trial is to assess the safety and tolerability of a single dose of BFB-101. This will be evaluated by monitoring for dose-limiting toxicities, treatment-emergent adverse events (TEAEs), and serious adverse events (SAEs) over a long-term follow-up period of 5 years. Secondary objectives include assessing preliminary efficacy across several domains: * Change from baseline in functional motor and developmental assessments (e.g., GMFM-88, Bayley Scales) * Evaluation of global clinical impression and caregiver-reported outcomes * Biomarkers of disease activity and target engagement (as available) * Time to progression or stabilization of motor milestones * Neuroimaging and electrophysiologic changes over time