Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec

Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog

“…A recent report described the development of an epithelioid neoplasm of the spinal cord 14 months after the intravenous administration of onasemnogene abeparvovec; although AAV vector genomes were present in most tumor cells, integration site analysis was inconclusive because of limited sample availability. 12 These findings are overall reassuring; however, the possible time between exposure to AAV vector and formation of an AAV-related cancer is unknown.…”

Integration and the risk of liver cancer—Is there a real risk?

“…In addition, the haemophilia clinical studies are further along than clinical studies for most other diseases and represent a larger number of subjects. HCC, 69 squamous cell tonsillar carcinoma, 70 acinic cell carcinoma (salivary gland), 71 B-cell acute lymphoblastic leukaemia (B-ALL) 72 and epithelioid neoplasm 73 have each been detected in a single patient between 1 and >5 years after vector administration (Table 1). The vector doses ranged from 1 × 10 12 to 1.1 × 10 14 vg/kg.…”

“…However, to date only two of these cases have been published as a complete case report. 69,73 The HCC that was observed in a haemophilia B subject after AAV gene therapy provides an opportunity to discuss the detailed analysis that is required to determine the diagnosis and the challenges of the molecular data analysis (Figure 2). In this Phase 3 study, haemophilia B subjects were treated with AAV5-hFIX-Padua at 2 × 10 13 vg/kg.…”

“…A more recent report of tumorigenesis following AAV administration was the development of an epithelioid neoplasm in a 16-month-old patient treated with onasamenogene aparvovec at 2 months of age (Zolgensma®). 73 The patient was determined to be at risk for spinal muscular atrophy (SMA) based on family history and the presence of low SMN2 copy numbers. Up to 13-months postvector infusion, the patient's motor development and neurological presentation were normal, but 1 month later, the patient presented with reduced motor symptoms, fussiness and urinary retention.…”

Toxicologic Neuropathology of Novel Biotherapeutics

“…128 A similar blood-nerve barrier protects nerves, while most somatic and autonomic ganglia lack a tight blood-ganglion barrier. 20,132,161 Accordingly, delivery of bio-derived therapeutics to most of the CNS and peripheral nervous system (PNS) requires specialized test articles or physical procedures to cross various neurovascular barriers. These include transient chemical or osmotic disruption of the BBB, non-viral (e.g., lipid nanoparticles) or viral-based (e.g., AAV vectors) carriers, and/or direct delivery into the neural (usually brain) parenchyma or cerebrospinal fluid (CSF).…”