title: Disease correction by combined neonatal intracranial AAV and systemic lentiviral gene therapy in Sanfilippo Syndrome type B mice.
abstract: Mucopolysaccharidosis type IIIB (MPS IIIB) or Sanfilippo Syndrome type B is a lysosomal storage disease resulting from the deficiency of N-acetyl glucosaminidase (NAGLU) activity. We previously showed that intracranial adeno-associated virus (AAV)-based gene therapy results in partial improvements of several aspects of the disease. In an attempt to further correct the disease, MPS IIIB mice were treated at 2-4 days of age with intracranial AAV2/5-NAGLU (IC-AAV), intravenous lentiviral-NAGLU (IV-LENTI) or the combination of both (BOTH). The BOTH group had the most complete biochemical and histological improvements of any treatment group. Compared with untreated MPS IIIB animals, all treatments resulted in significant improvements in motor function (rotarod) and hearing (auditory-evoked brainstem response). In addition, each treatment group had a significantly increased median life span compared with the untreated group (322 days). The combination arm had the greatest increase (612 days), followed by IC-AAV (463 days) and IV-LENTI (358 days). Finally, the BOTH group had nearly normal circadian rhythm measures with improvement in time to activity onset. In summary, targeting both the systemic and central nervous system disease of MPS IIIB early in life appears to be the most efficacious approach for this inherited metabolic disorder.
authors.affiliation: Department of Medicine, University of Florida, Gainesville, FL 32610, USA. coy.heldermon@medicine.ufl.edu
authors.forename: C D
authors.initials: CD
authors.lastname: Heldermon
authors.forename: E Y
authors.initials: EY
authors.lastname: Qin
authors.forename: K K
authors.initials: KK
authors.lastname: Ohlemiller
authors.forename: E D
authors.initials: ED
authors.lastname: Herzog
authors.forename: J R
authors.initials: JR
authors.lastname: Brown
authors.forename: C
authors.initials: C
authors.lastname: Vogler
authors.forename: W
authors.initials: W
authors.lastname: Hou
authors.forename: J L
authors.initials: JL
authors.lastname: Orrock
authors.forename: B E
authors.initials: BE
authors.lastname: Crawford
authors.forename: M S
authors.initials: MS
authors.lastname: Sands
mesh_terms: D000118:Acetylglucosaminidase / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002940:Circadian Rhythm; D000229:Dependovirus / Q000235:genetics*; D015316:Genetic Therapy; D005822:Genetic Vectors; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008099:Liver / Q000201:enzymology / Q000473:pathology; D008168:Lung / Q000201:enzymology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009084:Mucopolysaccharidosis III / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D016896:Treatment Outcome
chemical_list: D000118:Acetylglucosaminidase
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