Jun 18, 2021

A new article, “Emerging Immunogenicity and Genotoxicity Considerations of Adeno-Associated Virus Vector Gene Therapy for Hemophilia,” was published in the Journal of Clinical Medicine (JCM).

In this review, the authors discuss some of the primary considerations relevant to investigational gene therapies that employ adeno-associated viral (AAV) vectors, with particular focus on immunogenicity and genotoxicity – the former denotes the ability of a foreign substance to trigger an immune response, while the latter refers to a substances ability to damage genetic material.

AAV vectors act as delivery vehicles, carrying the genetic messaging that prompt the production of the factor VIII or factor IX proteins that are deficient in people with hemophilia A and B, respectively. Ideally, AAVs deliver this genetic material into living cells to sustain a therapeutic effect that is free of unintended adverse reactions in the short and long term. The challenge, and source of continued investigation by scientific researchers, is to better understand the nature of unwanted biological responses in patients who receive the one-time therapy. Foremost of these concerns are the potential for both innate and adaptive immune responses to AAVs and to the possible integration of the given vector into the genome of patients who have received the therapy. These types of responses could have safety and efficacy impacts, including inflammatory effects on the liver or the development of tumors or malignancies.  

Authors of the JCM paper review the evolution of AAV-based gene therapy, including descriptions of the unique vector types that continue to be investigated in both preclinical research and in clinical trials. The article also sheds light on the nuances of each vector and how they interact with a person’s natural immunity, including insights into the disparate responses elicited in hemophilia A, versus hemophilia B patients, all with an eye towards achieving a better understanding of long-term safety and efficacy.  

The authors go on to lay out various approaches to circumventing possible unwanted effects of AAV gene therapy, including enhanced screening for pre-existing neutralizing antibodies (Nabs), refinements to vector design, and adjustments in manufacturing that may allow the use of lower vector doses to forestall possible negative impacts of vector integration. They also reaffirm the importance of long-term follow-up of trial participants to glean valuable insights on the therapies’ overall impact for persons with hemophilia (PWH).   

“Gene transfer is likely to play an increasingly important role in the treatment of genetic diseases such as hemophilia. Important challenges remain to be overcome, such as finding solutions to immune‐related problems associated with viral vectors to provide safe, predictable, effective, and durable outcomes for PWH, concluded the authors. They added, “Despite the challenges that remain to be overcome, the potential of gene transfer to improve therapeutic outcomes is significant. Novel frontiers, such as tolerance induction, show promise for the development of curative treatments for hemophilia.”

The paper, which was published online in JCM on June 2, 2021, is open access – Follow this link to read the full review. 

Disclaimer: NHF provides periodic synopses of articles published in peer reviewed journals, the purpose of which is to highlight papers that cover a wide range of topics and speak to a broad spectrum of the inherited blood disorders community. Topics include shared decision making, gene therapy, health equity, and more. NHF hopes you find this content to be informative and engaging.

Any questions about the articles featured here should be directed to the publishing journal and/or the study authors. This content is for general information only. NHF does not give medical advice or engage in the practice of medicine. NHF under no circumstances recommends particular treatment for specific individuals and in all cases recommends that you consult your physician or local treatment center before pursuing any course of treatment.