Disease correction by AAV-mediated gene therapy in a new mouse model of mucopolysaccharidosis type IIID.
Gene therapy is a promising therapeutic alternative for Lysosomal Storage Disorders (LSD), as it is not necessary to correct the genetic defect in all cells of an organ to achieve therapeutically significant levels of enzyme in body fluids, from which non-transduced cells can uptake the protein correcting their enzymatic deficiency. Animal models are instrumental in the development of new treatments for LSD. Here we report the generation of the first mouse model of the LSD Muccopolysaccharidosis Type IIID (MPSIIID), also known as Sanfilippo syndrome type D. This autosomic recessive, heparan sulphate storage disease is caused by deficiency in N-acetylglucosamine 6-sulfatase (GNS). Mice deficient in GNS showed lysosomal storage pathology and loss of lysosomal homeostasis in the CNS and peripheral tissues, chronic widespread neuroinflammation, reduced locomotor and exploratory activity and shortened lifespan, a phenotype that closely resembled human MPSIIID. Moreover, treatment of the GNS-deficient animals with GNS-encoding adeno-associated viral (AAV) vectors of serotype 9 delivered to the cerebrospinal fluid completely corrected pathological storage, improved lysosomal functionality in the CNS and somatic tissues, resolved neuroinflammation, restored normal behaviour and extended lifespan of treated mice. Hence, this work represents the first step towards the development of a treatment for MPSIIID.
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Carles
C
Roca
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Sandra
S
Motas
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Sara
S
Marcó
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Albert
A
Ribera
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Víctor
V
Sánchez
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Xavier
X
Sánchez
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Joan
J
Bertolin
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Xavier
X
León
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.
Jennifer
J
Pérez
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Miguel
M
Garcia
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Pilar
P
Villacampa
Center of Animal Biotechnology and Gene Therapy.|Animal Health and Anatomy, School of Veterinary Medicine, Universitat Autònoma de Barcelona, 08193 Bellaterra.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Jesús
J
Ruberte
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Anna
A
Pujol
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Virginia
V
Haurigot
Center of Animal Biotechnology and Gene Therapy.|Departments of Biochemistry and Molecular Biology.|Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Barcelona 08036, Spain.
Fatima
F
Bosch
D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics / Q000627:therapeutic use; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D051379:Mice; D009084:Mucopolysaccharidosis III / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D010641:Phenotype; D013429:Sulfatases / Q000008:administration & dosage / Q000235:genetics*
D013429:Sulfatases; C018719:N-acetylglucosamine-6-sulfatase