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. 2014:1:14033.
doi: 10.1038/mtm.2014.33.

B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study

M Corti  1 , Me Elder  1 , Dj Falk  1 , L Lawson  1 , Bk Smith  2 , S Nayak  3 , Tj Conlon  1 , N Clément  1 , K Erger  1 , E Lavassani  1 , M Green  1 , Pa Doerfler  1 , Rw Herzog  1 , Bj Byrne  1
Affiliations

B-Cell Depletion is Protective Against Anti-AAV Capsid Immune Response: A Human Subject Case Study

M Corti et al. Mol Ther Methods Clin Dev. 2014.

Abstract

Gene therapy strategies for congenital myopathies may require repeat administration of adeno-associated viral (AAV) vectors in response to several limitations inherent to the clinical design: 1) administration of doses below therapeutic efficacy in patients enrolled in early phase clinical trials; 2) progressive reduction of the therapeutic gene expression over time as a result of increasing muscle mass in patients treated at a young age; and 3) a possibly faster depletion of pathogenic myofibers in this patient population. Immune responses triggered by the first vector administration, and to subsequent ones, represent a major obstacle for successful gene transfer in young patient population. Anti-capsid and anti-transgene product related humoral and cell-mediated responses have been previously observed in all preclinical models and human subjects who received gene therapy or ERT treatment for congenital myopathies. Immune responses may result in reduced efficacy of the gene transfer over time and/or may preclude for the possibility of re-administration of the same vector. This study presents a case of Pompe patient dosed with an AAV1-GAA vector after receiving Rituximab and Sirolimus to modulate the immune responses. A key finding of this single subject case report is the observation that B-cell ablation with rituximab prior to AAV vector exposure results in non-responsiveness to both capsid and transgene, therefore allowing the possibility of repeat administration in the future. This observation is significant for future gene therapy studies and establishes a clinically relevant approach to blocking immune responses to AAV vectors.

Keywords: AAV; Capsid antibody; Immunology; Pompe disease.

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Figures

Figure 1
Figure 1
Timeline: At 5.5 months of age the patient received an induction dose of Rituximab followed by daily oral Sirolimus. A monthly dose of IV immunoglobulin (IVIG) was also given. The patient continued the B-cell depletion regimen with Rituximab at 12 weeks intervals while receiving Sirolimus daily. At 6 months of age, following completion of Rituximab, the patient started on enzyme replacement therapy (ERT) at a dose of 20 mg/kg every 7–10 days. A brief course of methylprednisolone was given prior to and following AAV1-GAA intramuscular gene transfer to the diaphragm at 45 months of age.
Figure 2
Figure 2
A 3.5 year-old Pompe disease subject (solid lines, diamonds) received weekly administration of 375 mg/m2 of rituximab along with 10 mg/kg of methylprednisolone for 3 weeks prior to dosing with 5 × 1012 vg/kg of rAAV1-CMV-hGAA. The patient then received daily oral administration of 0.06–1 mg/m2 of Sirolimus through the study and continued B-cell depletion with Rituximab every 12 weeks. Five Pompe subjects (dash-dot lines, circles), age 2.5–15 years, received 1–5 × 1012 vg/kg of rAAV1-CMV-GAA without immune modulation, served as a control group. The light horizontal lines represent +2 SD above the population mean. (a) Circulating antibodies against AAV1. (b) Circulating antibodies against hGAA. (c) Antigen specific response assay versus AAV1. (d) Antigen specific response assay versus hGAA.
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