title: Prevalence of anti-adeno-associated virus serotype 8 neutralizing antibodies and arylsulfatase B cross-reactive immunologic material in mucopolysaccharidosis VI patient candidates for a gene therapy trial.
abstract: Recombinant vectors based on adeno-associated virus serotype 8 (AAV8) have been successfully used in the clinic and hold great promise for liver-directed gene therapy. Preexisting immunity against AAV8 or the development of antibodies against the therapeutic transgene product might negatively affect the outcomes of gene therapy. In the prospect of an AAV8-mediated, liver-directed gene therapy clinical trial for mucopolysaccharidosis VI (MPS VI), a lysosomal storage disorder caused by arylsulfatase B (ARSB) deficiency, we investigated in a multiethnic cohort of MPS VI patients the prevalence of neutralizing antibodies (Nab) to AAV8 and the presence of ARSB cross-reactive immunologic material (CRIM), which will either affect the efficacy of gene transfer or the duration of phenotypic correction. Thirty-six MPS VI subjects included in the study harbored 45 (62.5%) missense, 13 (18%) nonsense, 9 (12.5%) frameshift (2 insertions and 7 deletions), and 5 (7%) splicing ARSB mutations. The detection of ARSB protein in 24 patients out of 34 (71%) was predicted by the type of mutations. Preexisting Nab to AAV8 were undetectable in 19/33 (58%) analyzed patients. Twelve out of 31 patients (39%) tested were both negative for Nab to AAV8 and CRIM-positive. In conclusion, this study allows estimating the number of MPS VI patients eligible for a gene therapy trial by intravenous injections of AAV8.
authors: 1 Telethon Institute of Genetics and Medicine , 80078 Pozzuoli, Naples, Italy .
authors: Rita
authors: R
authors: Ferla
authors: Pamela
authors: P
authors: Claudiani
authors: Marco
authors: M
authors: Savarese
authors: Karen
authors: K
authors: Kozarsky
authors: Rossella
authors: R
authors: Parini
authors: Maurizio
authors: M
authors: Scarpa
authors: Maria Alice
authors: MA
authors: Donati
authors: Giovanni
authors: G
authors: Sorge
authors: John J
authors: JJ
authors: Hopwood
authors: Giancarlo
authors: G
authors: Parenti
authors: Simona
authors: S
authors: Fecarotta
authors: Vincenzo
authors: V
authors: Nigro
authors: Hatice Serap
authors: HS
authors: Sivri
authors: Ans
authors: A
authors: Van Der Ploeg
authors: Generoso
authors: G
authors: Andria
authors: Nicola
authors: N
authors: Brunetti-Pierri
authors: Alberto
authors: A
authors: Auricchio
mesh_terms: D057134:Antibodies, Neutralizing / Q000097:blood*; D015331:Cohort Studies; D003429:Cross Reactions; D004252:DNA Mutational Analysis; D000229:Dependovirus / Q000235:genetics / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods* / Q000592:standards; D006801:Humans; D007558:Italy; D009087:Mucopolysaccharidosis VI / Q000276:immunology* / Q000628:therapy; D009154:Mutation / Q000235:genetics; D020051:N-Acetylgalactosamine-4-Sulfatase / Q000097:blood* / Q000235:genetics; D009426:Netherlands; D018579:Patient Selection; D014421:Turkey
chemical_list: D057134:Antibodies, Neutralizing; D020051:N-Acetylgalactosamine-4-Sulfatase
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