TY - JOUR
T1 - Seven-year follow-up of durability and safety of AAV CNS gene therapy for a lysosomal storage disorder in a large animal
AU - Sánchez, Xavier
AU - Espada, Yvonne
AU - Roca, Carles
AU - Sánchez, Víctor
AU - León, Xavier
AU - Andaluz, Anna
AU - Bertolin, Joan
AU - Pérez, Jennifer
AU - Ribera, Albert
AU - Añor, Sonia
AU - Carretero, Ana
AU - Elias, Gemma
AU - Jaén, Maria Luisa
AU - Pumarola, Martí
AU - Marcó, Sara
AU - Molas, Maria
AU - Haurigot, Virginia
AU - Garcia, Miguel
AU - Bosch, Fatima
AU - Navarro, Marc
N1 - Publisher Copyright:
© 2021 The Authors
PY - 2021/12/10
Y1 - 2021/12/10
N2 - 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.
AB - 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.
KW - mucopolysaccharidosis type IIIA
KW - lysosomal storage disease
KW - safety
KW - cerebrospinal fluid
KW - dorsal root ganglia
KW - durability
KW - gene therapy
KW - brain
KW - adeno-associated viral vector
KW - central nervous system
UR - http://www.scopus.com/inward/record.url?scp=85122675184&partnerID=8YFLogxK
U2 - 10.1016/j.omtm.2021.09.017
DO - 10.1016/j.omtm.2021.09.017
M3 - Article
C2 - 34761052
SN - 2329-0501
VL - 23
SP - 370
EP - 389
JO - Molecular Therapy - Methods and Clinical Development
JF - Molecular Therapy - Methods and Clinical Development
ER -