Adeno-associated virus serotype 9 antibodies in patients screened for treatment with onasemnogene abeparvovec

Abstract

Spinal muscular atrophy is a progressive, recessively inherited monogenic neurologic disease, the genetic root cause of which is the absence of a functional survival motor neuron 1 gene. Onasemnogene abeparvovec (formerly AVXS-101) is an adeno-associated virus serotype 9 vector-based gene therapy that delivers a fully functional copy of the human survival motor neuron gene. We report anti–adeno-associated virus serotype 9 antibody titers for patients with spinal muscular atrophy when they were screened for eligibility in the onasemnogene abeparvovec clinical trials (intravenous and intrathecal administration) and managed access programs (intravenous). Through December 31, 2019, 196 patients and 155 biologic mothers were screened for anti–adeno-associated virus serotype 9 binding antibodies with an enzyme-linked immunosorbent assay. Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests. The low percentage of patients with exclusionary antibody titers indicates that most infants with spinal muscular atrophy type 1 should be able to receive onasemnogene abeparvovec. Retesting may identify patients whose antibody titers later decrease to below the threshold for treatment, and retesting should be considered for patients with anti–adeno-associated virus serotype 9 antibody titers >1:50.

Evaluation of the Humoral Response to Adeno-Associated Virus-Based Gene Therapy Modalities Using Total Antibody Assays

“…Of these, 15 patients (7.7%) and 23 biologic mothers (14.8%) had titers >1:50 on their initial screening tests. Eleven patients (5.6%) had elevated titers on their final screening tests (57).…”

Expert recommendations and clinical considerations in the use of onasemnogene abeparvovec gene therapy for spinal muscular atrophy

“…51 Screening results from the onasemnogene abeparvovec clinical trials and the managed access program through December 31, 2019, yielded 15 of 196 patients (7.7%) with exclusionary titers (>1:50). 52,53 When onasemnogene abeparvovec treatment is within the goals of the family and treating physician, retesting titers for patients with elevated baseline anti-AAV9 antibody titers may also be considered. Although the half-life of passively acquired immunoglobulin G (IgG) antibodies ranges from 35 to 40 days, 54 the time course of the clearance of anti-AAV9 antibodies has not been established.…”

“…The other US laboratory defined samples with less than 1:25 titers as seronegative. 53 Recommendation: The interpretation of anti-AAV9 antibody titers is based on assay and laboratory cutoffs. Repeat testing can be considered for those who initially have elevated titers depending on the specific clinical scenario.…”

“… 51 Screening results from the onasemnogene abeparvovec clinical trials and the managed access program through December 31, 2019, yielded 15 of 196 patients (7.7%) with exclusionary titers (>1:50). 52 , 53 …”

The DMD gene and therapeutic approaches to restore dystrophin

“…These vectors enable systemic gene delivery with a multiple-tissue-targeting ability, such as retina, CNS, liver, and muscle [28] ; moreover, the high infection efficiency and the large encapsulation capacity make AAVs the most promising vectors for delivering modified genes [26] . AAV9 is the common vector in neuromuscular gene therapy considering its potent tropism for the neuromuscular system, and lower prevalence of high levels, pre-existing, neutralizing AAV9 antibodies in patients [29] .…”