Cell-Mediated Immunity to NAGLU Transgene Following Intracerebral Gene Therapy in Children With Mucopolysaccharidosis Type IIIB Syndrome.

Marie-Lise Gougeon,Kumaran Deiva,Marc Tardieu,Jean-Michel Heard,Michel Zérah,Cécile Artaud,Jérome Ausseil,Béatrice Poirier-Beaudouin

doi:10.3389/fimmu.2021.655478

Abstract

Mucopolysaccharidosis type IIIB syndrome (Sanfilippo disease) is a rare autosomic recessif disorder caused by mutations in the α-N-acetylglucosaminidase (NAGLU) gene coding for a lysosomal enzyme, leading to neurodegeneration and progressive deterioration of cognitive abilities in affected children. To supply the missing enzyme, several recent human gene therapy trials relied on the deposit of adeno-associated virus (AAV) vectors directly into the brain. We reported safety and efficacy of an intracerebral therapy in a phase 1/2 clinical trial (https://clinicaltrials.gov/ct2/show/NCT03300453), with a recombinant AAV serotype 2/5 (rAAV2/5) coding human NAGLU in four children with MPS IIIB syndrome receiving immunosuppression. It was reported that AAV-mediated gene therapies might elicit a strong host immune response resulting in decreased transgene expression. To address this issue, we performed a comprehensive analysis of cellular immunity and cytokine patterns generated against the therapeutic enzyme in the four treated children over 5.5 years of follow-up. We report the emergence of memory and polyfunctional CD4+ and CD8+ T lymphocytes sensitized to the transgene soon after the start of therapy, and appearing in peripheral blood in waves throughout the follow-up. However, this response had no apparent impact on CNS transgene expression, which remained stable 66 months after surgery, possibly a consequence of the long-term immunosuppressive treatment. We also report that gene therapy did not trigger neuroinflammation, evaluated through the expression of cytokines and chemokines in patients’ CSF. Milder disease progression in the youngest patient was found associated with low level and less differentiated circulating NAGLU-specific T cells, together with the lack of proinflammatory cytokines in the CSF. Findings in this study support a systematic and comprehensive immunomonitoring approach for understanding the impact immune reactions might have on treatment safety and efficacy of gene therapies.

Highlights

Mucopolysaccharidosis type IIIB syndrome is a rare autosomic recessif lysosomal storage disorder with predominant neurological manifestation in affected children
These results led to the assessment of safety and efficacy of a novel intracerebral therapy in a phase 1/2 uncontrolled clinical trial, in which four children with MPSIIIB syndrome were enrolled to receive intraparenchymal deposits of a recombinant associated virus (AAV) vector serotype 2/5 encoding human NAGLU combined with immunosuppression (ClinicalTrials.gov Identifier: NCT03300453)
Considering that neutralizing antibodies against adeno-associated viral vector serotype 5 (AAV5) were not detected in serum samples collected at inclusion or during follow-up [20], we thought important to perform a comprehensive analysis of cellular immune response

Summary

Introduction

Mucopolysaccharidosis type IIIB syndrome ( known as Sanfilippo syndrome type B) is a rare autosomic recessif lysosomal storage disorder with predominant neurological manifestation in affected children. In preclinical studies in MPS IIIB mice [8, 9] and dogs [10, 11], beneficial biochemical and neurological effects with intracerebral gene therapy administered via a recombinant AAV vector encoding NAGLU were observed, associated with the release of therapeutic enzyme from transduced brain cells These results led to the assessment of safety and efficacy of a novel intracerebral therapy in a phase 1/2 uncontrolled clinical trial, in which four children with MPSIIIB syndrome were enrolled to receive intraparenchymal deposits of a recombinant AAV vector serotype 2/5 (rAAV2/5) encoding human NAGLU combined with immunosuppression (ClinicalTrials.gov Identifier: NCT03300453). Good tolerance, sustained NAGLU production and milder disease in the patient treated at very early stage were confirmed after a 5.5 years follow-up (Deiva et al Submitted to publication)

Methods

Results

Conclusion