Progress and prospects: gene therapy for genetic diseases with helper-dependent adenoviral vectors

摘要

Preclinical studies in small and large animal models using helper-dependent adenoviral vectors (HDAds) have generated promising results for the treatment of genetic diseases. However, clinical translation is complicated by the dose-dependent, capsid-mediated acute toxic response following systemic vector injection. With the advancements in vectorology, a better understanding of vector-mediated toxicity, and improved delivery methods, HDAds may emerge as an important vector for gene therapy of genetic diseases and this report highlights recent progress and prospects in this field. In briefProgress class="unordered" style="list-style-type:disc" id="L1">HDAds provide stable, long-term transgene expression in small and large animal models without chronic toxicity for liver-directed gene therapy.High vector doses are required for efficient hepatocyte transduction by systemic administration.Strategies to improve the therapeutic index of HDAd are available or currently under investigation for liver-directed gene therapy.High-efficiency pulmonary transduction and clinically relevant end points can be achieved delivering HDAd in conjunction with tight junction opening agents for CF gene therapy.HDAd delivered with an intracorporeal nebulizing catheter results in high-efficiency transduction of the respiratory epithelium in large animals.Encouraging results have been obtained with HDAd for brain- and muscle-directed gene therapy in animal models.Prospects class="unordered" style="list-style-type:disc" id="L2">A better understanding of the acute innate response will provide new targets for pharmacological blockade to improve the therapeutic index of the vector.Further optimization of preferential liver targeting by HDAd through balloon catheter delivery has the potential of providing a clinically attractive method of vector delivery.Further assessment of Ad PEGylation and modulation of the liver fenestrations may provide attractive strategies to increase the therapeutic index of the vector.Capsid modification to increase the affinity of Ad for hepatocytes has the potential to improve safety and efficacy.A large animal model for cystic fibrosis is needed to fully evaluate safety and efficacy of airway delivery of HDAd.