Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy. It has been widely used in preclinical studies and over 100 clinical trials. There are already several approved gene therapy products, e.g., ZOLGENSMA, highlighting the enormous potential of AAV gene therapy. For long, AAV has been seen as a relatively non-immunogenic vector. However, recent studies have shown that immune response to AAV vectors could be a bottleneck of AAV gene therapy. Immune response to AAV could lead to severe toxicity and early euthanasia of animals, as well as loss of efficacy over time. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment. More recently, liver toxicity due to immune response may have led to four deaths of patients from an AAV gene therapy clinical trial.
In light of the ever-increasing AAV gene therapy clinical activity, this collection aims to tackle the following key issues around AAV immunogenicity. 1) Due to the exposure of humans to wildtype AAV, pre-existing antibodies are prevalent in the population, limiting the eligibility of patients and the market size of AAV gene therapy. 2) Antibodies can neutralize transgene products and T cells can eliminate transgene-expressing cells, resulting in loss of efficacy over time. 3) Since the durability of AAV gene therapy is in question, there may be a need for redosing, which is limited by immunity against AAV capsids and transgene products. 4) Also, AAV immunity has been shown to cause severe toxicity, manifested as liver and kidney injury, thrombocytopenia, resulting in deaths of non-human primates and patients. 5) In addition, due to the lack of robust preclinical models, it is challenging to predict the immune responses of patients following AAV delivery. 6) Novel methods, e.g. de-targeting DC, TLR9 inhibition, CpG removal, capsid engineering, IgG degradation, B and T cell depletion, immune tolerance induction, to reduce immunogenicity, have been developed.
We welcome the submission of Original Research, Perspective, Reviews, and Mini-Reviews articles, which cover, but are not limited to, the following topics:
• How pre-existing antibodies against AAV capsids present a problem to gene delivery
• How immune response causes toxicity and loss of efficacy over time
• How empty/full capsid ratio and impurity affects the immunogenicity
• How immune response create challenges for redosing
• What roles antibodies, T cells, and complement system play in immune response against AAV
• The latest advance in methods to circumvent or reduce immunogenicity
• What metrics are being used to assess immunogenicity and how to improve them
• How preclinical models can be optimized to enable comparisons of immunogenicity between species and predict clinical results
• Regulatory considerations for AAV immunogenicity
• Clinical experience in measuring and managing immune responses against AAV
Topic editor Li Ou is employed by Capsida Biotherapeutics. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
Recombinant adeno-associated virus (AAV) is a promising delivery vehicle for in vivo gene therapy. It has been widely used in preclinical studies and over 100 clinical trials. There are already several approved gene therapy products, e.g., ZOLGENSMA, highlighting the enormous potential of AAV gene therapy. For long, AAV has been seen as a relatively non-immunogenic vector. However, recent studies have shown that immune response to AAV vectors could be a bottleneck of AAV gene therapy. Immune response to AAV could lead to severe toxicity and early euthanasia of animals, as well as loss of efficacy over time. In clinical studies, pre-existing antibodies against AAV capsids exclude many patients from receiving the treatment. More recently, liver toxicity due to immune response may have led to four deaths of patients from an AAV gene therapy clinical trial.
In light of the ever-increasing AAV gene therapy clinical activity, this collection aims to tackle the following key issues around AAV immunogenicity. 1) Due to the exposure of humans to wildtype AAV, pre-existing antibodies are prevalent in the population, limiting the eligibility of patients and the market size of AAV gene therapy. 2) Antibodies can neutralize transgene products and T cells can eliminate transgene-expressing cells, resulting in loss of efficacy over time. 3) Since the durability of AAV gene therapy is in question, there may be a need for redosing, which is limited by immunity against AAV capsids and transgene products. 4) Also, AAV immunity has been shown to cause severe toxicity, manifested as liver and kidney injury, thrombocytopenia, resulting in deaths of non-human primates and patients. 5) In addition, due to the lack of robust preclinical models, it is challenging to predict the immune responses of patients following AAV delivery. 6) Novel methods, e.g. de-targeting DC, TLR9 inhibition, CpG removal, capsid engineering, IgG degradation, B and T cell depletion, immune tolerance induction, to reduce immunogenicity, have been developed.
We welcome the submission of Original Research, Perspective, Reviews, and Mini-Reviews articles, which cover, but are not limited to, the following topics:
• How pre-existing antibodies against AAV capsids present a problem to gene delivery
• How immune response causes toxicity and loss of efficacy over time
• How empty/full capsid ratio and impurity affects the immunogenicity
• How immune response create challenges for redosing
• What roles antibodies, T cells, and complement system play in immune response against AAV
• The latest advance in methods to circumvent or reduce immunogenicity
• What metrics are being used to assess immunogenicity and how to improve them
• How preclinical models can be optimized to enable comparisons of immunogenicity between species and predict clinical results
• Regulatory considerations for AAV immunogenicity
• Clinical experience in measuring and managing immune responses against AAV
Topic editor Li Ou is employed by Capsida Biotherapeutics. All other Topic Editors declare no competing interests with regards to the Research Topic subject.
