Pilocytic Astrocytoma in a Child with Spinal Muscular Atrophy Treated with Onasemnogene Abeparvovec.

in Molecular therapy : the journal of the American Society of Gene Therapy by Dorothea Holzwarth, Gabriele Calaminus, Johannes Friese, Thomas Sejersen, Hildegard Büning, Philipp John-Neek, Antonella Lucía Bastone, Michael Rothe, Keith Mansfield, Silvana Libertini, Valerie Dubost, Brent Kuzmiski, Iulian Alecu, Ivan Labik, Janbernd Kirschner

TLDR

  • A patient diagnosed with a grade 1 pilocytic astrocytoma after receiving onasemnogene abeparvovec treatment for SMA showed low-level vector persistence in the tumor tissue, indicating no causal link to tumorigenesis.
  • Future studies will focus on elucidating the underlying causes of tumorigenesis and exploring potential mechanisms for tumor development.

Abstract

Spinal muscular atrophy (SMA) is a severe neuromuscular disease, leading to progressive muscle weakness and potentially early mortality if untreated. Onasemnogene abeparvovec is a recombinant adeno-associated virus serotype 9 (rAAV9)-based gene therapy that has demonstrated improvements in survival and motor function for SMA patients. Here, we present a case of a patient diagnosed with a grade 1 pilocytic astrocytoma at the age of 2 years, approximately 8 months after onasemnogene abeparvovec treatment. Although vector genomes delivered by rAAVs persist primarily as episomes, rare integration events have been linked to tumor formation in neonate murine models. Therefore, we investigated the presence and possible integration of onasemnogene abeparvovec in formalin-fixed paraffin embedded (FFPE) and frozen tumor samples. In situ hybridization demonstrated variable transduction levels in individual tumor cells while droplet digital PCR measured an average vector copy number ranging from 0.7-4.9 vector genomes/diploid genome. Integration site analysis identified a low number of integration sites that were not conserved between technical replicates, nor between FFPE and frozen samples, indicating that cells hosting integrating vector genomes represent a minority in the overall cell population. Thus, molecular analysis of the tumor tissue suggests that tumorigenesis was causally independent of the administration of onasemnogene abeparvovec.

Overview

  • The study presents a case of a patient diagnosed with a grade 1 pilocytic astrocytoma after receiving onasemnogene abeparvovec treatment for spinal muscular atrophy (SMA).
  • The study investigates the presence and possible integration of onasemnogene abeparvovec in the tumor tissue samples and its potential link to tumorigenesis.
  • The study aims to determine whether the administration of onasemnogene abeparvovec contributed to the development of the tumor or was causally independent of it.

Comparative Analysis & Findings

  • In situ hybridization showed variable transduction levels in individual tumor cells, indicating a low frequency of vector genomes in the tumor tissue.
  • Droplet digital PCR measured an average vector copy number ranging from 0.7-4.9 vector genomes/diploid genome, suggesting a relatively low-level of vector persistence.
  • Integration site analysis identified a low number of integration sites that were not conserved between technical replicates and between FFPE and frozen samples, indicating a minority of cells hosting integrating vector genomes.

Implications and Future Directions

  • The study's findings suggest that the administration of onasemnogene abeparvovec did not contribute to the development of the tumor, and tumorigenesis was likely causally independent of the gene therapy.
  • Future studies should focus on elucidating the underlying causes of tumorigenesis in this patient and exploring potential mechanisms for tumor development in other patients receiving onasemnogene abeparvovec.
  • Given the low frequency of vector genomes in the tumor tissue, ongoing monitoring and follow-up of patients receiving onasemnogene abeparvovec may be necessary to detect potential rare events.
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