Impact of preexisting antibodies against AAV in mothers, infants and human milk

Topic:

Translational Research

Poster Number: P166

Author(s):

Stephanie Salabarria, BS, University of Florida, Kirsten Coleman, MBA, University of Florida, Lochlin Cravey, MS, University of Florida, Vivian Valcarce, MD, University of Alabama, Carmen Astudillo Leon, MD, University of Florida, Megan Wichman, BA, University of Florida, Lauren Steward Stafford, PhD, University of Florida, Jessica Ruoss, MD, University of Florida, Manuela Corti, PT, PhD, University of Florida, Joseph Larkin, PhD, University of Florida, Barry Byrne, MD, PhD, University of Florida

Background

Gene therapy using recombinant adeno-associated virus (rAAV) vectors is a feasible treatment for pediatric patients with rare monogenic diseases, like in the case of patients with spinal muscular atrophy (SMA). Onasemnogene-abeparvovec (OA, Zolgensma) is a rAAV9 based systemic gene therapy for the treatment of SMA. Early diagnosis and treatment of infants with SMA with the use of OA and other medications is possible thanks to newborn screening programs. However, 40- 70% of the population is estimated to have pre-existing exposure to AAV.Pre-existing circulating and neutralizing antibodies can either abate treatment, preventing therapeutic levels of expression, or cause complications associated with a humoral and cellular immune response. Therefore, preexisting humoral immunity to AAV excludes patients from receiving rAAV based gene therapies. The exact seroprevalence in mother-infant pairs has not been described in the literature. Further, seroconversion of a seronegative infant through breastfeeding has been a concern, despite lack of literature and minimal risk of IgG reaching the circulation after ingestion (Van de Perre, 2003).

Objectives

In this two-part study, we collected blood samples immediately post-partum from mother and infant pairs as well as plasma and breastmilk samples from lactating mothers to: 1)Quantify circulating IgG and IgM antibodies against AAV9 in blood samples from mother-infant pairs and 2)Quantify circulating IgG and IgM antibodies against AAV9 and AAVrh74 in plasma and human milk samples and determine the correlation between those.

Results

Mother-infant blood samples: maternal blood and cord blood samples from 73 mother-baby pairs were analyzed. Sixty-seven % (N=49) (of maternal samples were seropositive for anti-AAV9 IgG and 59% (N=43) of infant samples were found to be seropositive (*above 50 U/mL).

AAV Antibodies in human milk: Plasma and human milk samples from thirty-one mothers were analyzed. In plasma samples, 24 (77%) mothers had anti-AAV9 IgG >50 U/mL while 26 (84%) mothers had anti-AAVrh74 IgG >50 U/mL. There was > 90% decrease in both anti-AAV IgG and IgM antibodies in breastmilk when compared to plasma, regardless of AAV serotype.

Conclusions

A strong correlation was identified between the presence of IgG in mothers and infants.. Breastfeeding alone does not result in an increased seroconversion risk in the case of term infants born to seropositive mothers.