Safety profile of recombinant adeno-associated viral vectors: focus on alipogene tiparvovec (Glybera^®)

Abstract

There has been great interest over the past two decades in developing gene therapies (GTs) to treat a variety of diseases; however, translating research findings into clinical treatments have proved to be a challenge. A major milestone in the development of GT has been achieved with the approval of alipogene tiparvovec (Glybera^®) in Europe for the treatment of familial lipoprotein lipase deficiency. At this important stage with the evolution of GT into the clinic, this review will examine the safety aspects GT with adeno-associated virus (AAV) vectors. The topics that will be covered include acute reactions, immunological reactions to the AAV capsid and expressed transgene, viral biodistribution and shedding, DNA integration and carcinogenicity. These safety aspects of GT will be discussed with a focus on alipogene tiparvovec, in addition to other AAV vector GT products currently in clinical development.

Keywords::

• adeno-associated viral vectors
• alipogene tiparvovec
• AAV1-LPLS^447X
• gene therapy
• lipoprotein lipase
• lipoprotein lipase deficiency

Financial & competing interests disclosure

F Salmon, K Grosios and H Petry are all employees of uniQure, Amsterdam, The Netherlands. Funding support for the preparation of the manuscript was provided by uniQure. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Writing assistance was provided by GK PharmaComm and funded by uniQure.

Key issues

• Intramuscular administration of alipogene tiparvovec in lipoprotein lipase deficiency patients is well tolerated. The most frequent adverse events observed in the clinical trials were injection-associated local reactions that were directly related to the administration procedure and were resolved within a few days after injection.

• Innate immune responses are unlikely to cause major clinical concerns for adeno-associated virus gene therapy products.

• Humoral responses and their impact on transgene expression are dependent on the particular vector used, route of administration and target organ.

• Administration of alipogene tiparvovec to skeletal muscle is not associated with increase in markers of inflammatory response or tissues damage and while transient local and systemic immune responses were observed in some patients, transgene expression and clinical efficacy were maintained.

• DNA integration analysis, preclinical studies and clinical experience to date demonstrate that no specific carcinogenic profile is associated with adeno-associated virus gene therapy products.