title: Neutralizing Antibodies Against Adeno-Associated Viral Capsids in Patients with mut Methylmalonic Acidemia.
abstract: Isolated methylmalonic acidemia (MMA), a group of autosomal recessive inborn errors of metabolism, is most commonly caused by complete (mut(0)) or partial (mut(-)) deficiency of the enzyme methylmalonyl-CoA mutase (MUT). The severe metabolic instability and increased mortality experienced by many affected individuals, especially those with mut(0) MMA, has led centers to use elective liver transplantation as a treatment for these patients. We have previously demonstrated the efficacy of systemic adeno-associated viral (AAV) gene delivery as a treatment for MMA in a murine model and therefore sought to survey AAV antibody titers against serotypes 2, 8, and 9 in a group of well-characterized MMA patients, accrued via a dedicated natural history study ( clinicaltrials.gov ID: NCT00078078). Plasma samples provided by 42 patients (8 mut(-) and 34 mut(0); 10 had received organ transplantation), who ranged in age between 2 and 31 years, were analyzed to examine AAV2 (n = 35), AAV8 (n = 41), and AAV9 (n = 42) antibody titers. In total, the seroprevalence of antibodies against AAV2, AAV8, or AAV9 was 20%, 22%, and 24%, respectively. We observed a lower-than-expected seropositivity rate (titers ≥1:20) in the pediatric MMA patients (2-18 years) for both AAV2 (p < 0.05) and AAV8 (p < 0.01) neutralizing antibodies (NAbs) compared with historical controls. Those with positive NAb titers were typically older than 18 years (p < 0.05 all serotypes) or had received solid organ transplantation (p < 0.01 AAV8, AAV9). The mut(0) patients who had not been transplanted (n = 24)-that is, the subset with the greatest need for improved treatments-represented the seronegative majority, with 21 out of 24 patients lacking Abs against all AAV capsids tested. The unexpected lack of NAbs against AAV in this patient population has encouraging implications for systemic gene delivery as a treatment for mut MMA.
authors.affiliation: 1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Harrington
authors.affiliation: 1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Sloan
authors.affiliation: 1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Irini
authors.initials: I
authors.lastname: Manoli
authors.affiliation: 1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Chandler
authors.affiliation: 2 Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Mark
authors.initials: M
authors.lastname: Schneider
authors.affiliation: 3 Metabolism, Infection and Immunity Unit, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: McGuire
authors.affiliation: 2 Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: Roberto
authors.initials: R
authors.lastname: Calcedo
authors.affiliation: 2 Gene Therapy Program, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania , Philadelphia, Pennsylvania.
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.affiliation: 1 Organic Acid Research Section, Medical Genomics and Metabolic Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland.
authors.forename: Charles P
authors.initials: CP
authors.lastname: Venditti
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000276:immunology* / Q000628:therapy; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology*; D002213:Capsid / Q000276:immunology*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003429:Cross Reactions / Q000276:immunology; D000229:Dependovirus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects* / Q000379:methods; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology*; D005838:Genotype; D006801:Humans; D008297:Male; D008765:Methylmalonyl-CoA Mutase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D055815:Young Adult
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D008765:Methylmalonyl-CoA Mutase