Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders
Lara Marrone, Paolo Marchi, Mimoun Azzouz
Abstract
INTRODUCTION: . Yet, despite the success of recent AAV-based clinical trials, the clinical use of these vectors has been limited. For instance, the AAV packaging capacity is restricted to ~4.7 kb, making it a substantial challenge to deliver large gene products. AREAS COVERED: In this review, we explore established and emerging strategies that circumvent the packaging limit of AAVs to make them effective vehicles for gene replacement therapy of monogenic disorders, with a particular focus on diseases affecting the nervous system. We report historical references, design remarks, as well as strengths and weaknesses of these approaches. We additionally discuss examples of neurological disorders for which such strategies have been attempted. EXPERT OPINION: The field of AAV-gene therapy has experienced enormous advancements in the last decade. However, there is still ample space for improvement aimed at overcoming existing challenges that are slowing down the progressive trajectory of this field.