Evading the AAV Immune Response in Mucopolysaccharidoses.

Matthew Piechnik,Yasuhiko Ago,Hidenori Ohnishi,Shunji Tomatsu,Norio Kawamoto,Kazuki Sawamoto

doi:10.3390/ijms21103433

Abstract

The humoral immune response elicited by adeno-associated virus (AAV)-mediated gene therapy for the treatment of mucopolysaccharidoses (MPS) poses a significant challenge to achieving therapeutic levels of transgene expression. Antibodies targeting the AAV capsid as well as the transgene product diminish the production of glycosaminoglycan (GAG)-degrading enzymes essential for the treatment of MPS. Patients who have antibodies against AAV capsid increase in number with age, serotype, and racial background and are excluded from the clinical trials at present. In addition, patients who have undergone AAV gene therapy are often excluded from the additional AAV gene therapy with the same serotype, since their acquired immune response (antibody) against AAV will limit further efficacy of treatment. Several methods are being developed to overcome this immune response, such as novel serotype design, antibody reduction by plasmapheresis and immunosuppression, and antibody evasion using empty capsids and enveloped AAV vectors. In this review, we examine the mechanisms of the anti-AAV humoral immune response and evaluate the strengths and weaknesses of current evasion strategies in order to provide an evidence-based recommendation on evading the immune response for future AAV-mediated gene therapies for MPS.

Highlights

Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders (LSDs) caused by a deficiency in an enzyme responsible for the catabolism of glycosaminoglycans (GAGs)
We have reviewed the mechanisms of the associated virus (AAV) humoral immune response (Figure 1) as well as evaluated the current immune evasion strategies for MPS
The immune response to AAV vector-mediated gene therapy diminishes the efficacy of transgene production and limits the therapeutic success which we can achieve in current gene therapy

Summary

Introduction

Mucopolysaccharidoses (MPS) are a group of rare lysosomal storage disorders (LSDs) caused by a deficiency in an enzyme responsible for the catabolism of glycosaminoglycans (GAGs). Current therapy options for MPS patients include enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT) [2]. HSCT is considered the standard of care for patients with MPS IH and an optional treatment for those with Hurler/Scheie syndrome (MPS IH/S) and Scheie syndrome (MPS-IS) (attenuated phenotypes of MPS I), MPS II, MPS IVA, MPS VI, and MPS VII [14]. More than 1000 patients with MPS have undergone HSCT to treat their disease [15]. HSCT has several critical issues: (1) finding the appropriate donor, (2) risks of graft versus host disease and rejection, (3) limited impact on bone lesions, and (4) the requirement of well-trained staff and facilities. Limitations of ERT and HSCT are well observed; novel therapeutic options with gene therapy are being pursued in preclinical and clinical trials (Table 1)

Injection Method

Anti-AAV Antibodies and the AAV Capsid

Transgene Product Immune Response

Evading the Anti-Capsid Immune Response

Findings

Conclusions