Helper-Dependent Adenoviral Vectors: Recent Advances and Emerging Applications

Helper-dependent adenoviral vectors (HDAdVs), which lack all viral coding sequences, enable the delivery of up to 35 kilobases (kb) of therapeutic DNA into target cells. This large packaging capacity facilitates the transfer of complex, large, or even multiple transgenes. Despite the technical complexity of their production, HDAdVs have been extensively evaluated in numerous preclinical studies, and several clinical trials have recently been initiated. This review provides a comprehensive, state-of-the-art overview of recent advances in the HDAdVs technology. It summarizes key strategies for vector development, including capsid engineering and improvements in production methodologies. Furthermore, it reviews preclinical in vivo studies with a focus on vector design, target indications, and therapeutic outcomes. Most preclinical applications have focused on targeting the liver and hematopoietic stem cells; however, additional organ systems and vaccination approaches based on HDAdVs are also being actively explored. In addition to preclinical progress, three recently initiated clinical trials using HDAdVs targeting knee osteoarthritis, chronic granulomatous disease, and solid tumors are highlighted. Nevertheless, several challenges must be addressed to enable broader clinical translation of HDAdVs. These include the complexity of large-scale manufacturing, achieving efficient and specific vector targeting, and overcoming host immune responses. In conclusion, HDAdV-based vector systems hold considerable promise for the treatment of a wide range of diseases. Continued technological advancements, including the development of next-generation adenoviral platforms and the integration of precision gene therapy approaches, are likely to further enhance their potential as versatile biotherapeutic tools.