TY - JOUR
T1 - Whole body correction of mucopolysaccharidosis IIIA by intracerebrospinal fluid gene therapy
AU - Haurigot, Virginia
AU - Marcó, Sara
AU - Ribera Sanchez, Albert
AU - Garcia Martinez, Miguel
AU - Ruzo, Albert
AU - Villacampa, Pilar
AU - Ayuso Lopez, Eduardo
AU - Añor Torres, Sonia
AU - Andaluz Martinez, Ana Maria
AU - Pineda, Mercedes
AU - García-Fructuoso, Gemma
AU - Molas, Maria
AU - Maggioni, Luca
AU - Muñoz, Sergio
AU - Motas, Sandra
AU - Ruberte Paris, Jesus
AU - Mingozzi, Federico
AU - Pumarola Batlle, Marti
AU - Bosch Tubert, Maria Fatima
N1 - Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.
PY - 2013/8/1
Y1 - 2013/8/1
N2 - For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.
AB - For most lysosomal storage diseases (LSDs) affecting the CNS, there is currently no cure. The BBB, which limits the bioavailability of drugs administered systemically, and the short half-life of lysosomal enzymes, hamper the development of effective therapies. Mucopolysaccharidosis type IIIA (MPS IIIA) is an autosomic recessive LSD caused by a deficiency in sulfamidase, a sulfatase involved in the stepwise degradation of glycosaminoglycan (GAG) heparan sulfate. Here, we demonstrate that intracerebrospinal fluid (intra-CSF) administration of serotype 9 adenoassociated viral vectors (AAV9s) encoding sulfamidase corrects both CNS and somatic pathology in MPS IIIA mice. Following vector administration, enzymatic activity increased throughout the brain and in serum, leading to whole body correction of GAG accumulation and lysosomal pathology, normalization of behavioral deficits, and prolonged survival. To test this strategy in a larger animal, we treated beagle dogs using intracisternal or intracerebroventricular delivery. Administration of sulfamidase-encoding AAV9 resulted in transgenic expression throughout the CNS and liver and increased sulfamidase activity in CSF. High-titer serum antibodies against AAV9 only partially blocked CSF-mediated gene transfer to the brains of dogs. Consistently, anti-AAV antibody titers were lower in CSF than in serum collected from healthy and MPS IIIA-affected children. These results support the clinical translation of this approach for the treatment of MPS IIIA and other LSDs with CNS involvement.
UR - http://www.scopus.com/inward/record.url?scp=84881228888&partnerID=8YFLogxK
U2 - 10.1172/JCI66778
DO - 10.1172/JCI66778
M3 - Article
SN - 0021-9738
VL - 123
SP - 3254
EP - 3271
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -