Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal

Sara Marcó, Virginia Haurigot, Maria Luisa Jaén, Albert Ribera, Víctor Sánchez, Maria Molas, Miguel Garcia, Xavier León, Carles Roca, Xavier Sánchez, Joan Bertolin, Jennifer Pérez, Gemma Elias, Marc Navarro, Ana Carretero, Martí Pumarola, Anna Andaluz, Yvonne Espada, Sonia Añor, Fatima Bosch

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)


Delivery of adeno-associated viral vectors (AAVs) to cerebrospinal fluid (CSF) has emerged as a promising approach to achieve widespread transduction of the central nervous system (CNS) and peripheral nervous system (PNS), with direct applicability to the treatment of a wide range of neurological diseases, particularly lysosomal storage diseases. Although studies in small animal models have provided proof of concept and experiments in large animals demonstrated feasibility in bigger brains, there is not much information on long-term safety or durability of the effect. Here, we report a 7-year study in healthy beagle dogs after intra-CSF delivery of a single, clinically relevant dose (2 × 1013 vg/dog) of AAV9 vectors carrying the canine sulfamidase, the enzyme deficient in mucopolysaccharidosis type IIIA. Periodic monitoring of CSF and blood, clinical and neurological evaluations, and magnetic resonance and ultrasound imaging of target organs demonstrated no toxicity related to treatment. AAV9-mediated gene transfer resulted in detection of sulfamidase activity in CSF throughout the study. Analysis at tissue level showed widespread sulfamidase expression and activity in the absence of histological findings in any region of encephalon, spinal cord, or dorsal root ganglia. Altogether, these results provide proof of durability of expression and long-term safety for intra-CSF delivery of AAV-based gene transfer vectors encoding therapeutic proteins to the CNS.

Original languageEnglish
Pages (from-to)370-389
Number of pages20
JournalMolecular Therapy - Methods and Clinical Development
Publication statusPublished - 10 Dec 2021


  • adeno-associated viral vector
  • brain
  • central nervous system
  • cerebrospinal fluid
  • dorsal root ganglia
  • durability
  • gene therapy
  • lysosomal storage disease
  • mucopolysaccharidosis type IIIA
  • safety


Dive into the research topics of 'Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal'. Together they form a unique fingerprint.

Cite this