title: Low-dose Gene Therapy Reduces the Frequency of Enzyme Replacement Therapy in a Mouse Model of Lysosomal Storage Disease.
abstract: Enzyme replacement therapy (ERT) is the standard of care for several lysosomal storage diseases (LSDs). ERT, however, requires multiple and costly administrations and has limited efficacy. We recently showed that a single high dose administration of adeno-associated viral vector serotype 8 (AAV2/8) is at least as effective as weekly ERT in a mouse model of mucopolysaccharidosis type VI (MPS VI). However, systemic administration of high doses of AAV might result in both cell-mediated immune responses and insertional mutagenesis. Here we evaluated whether the combination of low doses of AAV2/8 with a less frequent (monthly) than canonical (weekly) ERT schedule may be as effective as the single treatments at high doses or frequent regimen. A greater reduction of both urinary glycosaminoglycans, considered a sensitive biomarker of therapeutic efficacy, and storage in the myocardium and heart valves was observed in mice receiving the combined than the single therapies. Importantly, these levels of correction were similar to those we obtained in a previous study following either high doses of AAV2/8 or weekly ERT. Our data show that low-dose gene therapy can be used as a means to rarify ERT administration, thus reducing both the risks and costs associated with either therapies.
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Medical Genetics, Department of Translational Medicine (DISMET), "Federico II" University, Naples, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Alliegro
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Medical Genetics, Department of Translational Medicine (DISMET), "Federico II" University, Naples, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Ferla
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Edoardo
authors.initials: E
authors.lastname: Nusco
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: De Leonibus
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Medical Genetics, Department of Translational Medicine (DISMET), "Federico II" University, Naples, Italy.
authors.forename: Carmine
authors.initials: C
authors.lastname: Settembre
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Naples, Italy.|Medical Genetics, Department of Translational Medicine (DISMET), "Federico II" University, Naples, Italy.
authors.forename: Alberto
authors.initials: A
authors.lastname: Auricchio
mesh_terms: D000818:Animals; D003131:Combined Modality Therapy / Q000379:methods*; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy / Q000379:methods*; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006025:Glycosaminoglycans / Q000652:urine; D006801:Humans; D016464:Lysosomal Storage Diseases / Q000628:therapy* / Q000652:urine; D051379:Mice; D016896:Treatment Outcome
chemical_list: D006025:Glycosaminoglycans