Immunitrack co-authors new article in Molecular Therapy that sheds light on factors impacting AAV immunogenicity
Immunitrack proudly announces co-authorship with the U.S. Food and Drug Administration on a new article in Molecular Therapy entitled: ‘Differential T cell immune responses to deamidated adeno-associated virus vector’.
In the study, Immunitrack’s NeoScreen platform was used to elucidate how deamidation at specific sites in adeno-associated vector 9 (AAV9) can impact the immunogenicity, safety and efficacy of recombinant AAV-mediated gene therapy in certain patients.
By determining the stability of binding of wild-type vs. deamidated rAAV capsid epitopes across a wide range of HLA molecules, the study sheds new light on how clinical pre-screening and monitoring can be improved to better understand the immune responses that are seen in a small number of individuals treated with rAAV gene therapy.
Level of AAV capsid deamidation is extensive and increases through time independently of serotype and manufacturing systems.
Gene addition therapy has huge potential to provide single-dose cures for monogenic disorders. Recombinant AAVs (rAAVs) are among the most attractive vectors for in vivo gene delivery and replacement. So far, two AAV-based gene therapies have been approved by the FDA and European Medicines agency; Luxturna (Spark Therapeutics) and Zolgensma (Novartis) for the treatment of a rare inherited retinal dystrophy and spinal muscular atrophy, respectively.
However, despite these two approvals and almost 200 ongoing rAAV-based clinical trials for gene therapy, the clinical use of AAV vectors has been limited. This is in part due to widespread exposure of naturally occurring AAV throughout our lives, resulting in pre-existing immunity to AAVs in 30-60% of the human population. Natural infection with AAV is harmless, but exposure to large quantities of AAV administered by non-natural routes can present significant safety issues. For instance, deleterious capsid cytotoxic T lymphocyte responses have been involved in loss of efficacy and potentially liver toxicity.
Recent studies have demonstrated that rAAV capsid proteins undergo high levels of deamidation, including asparagine residues in some of the reported T cell epitopes. To understand how such post-translational modifications might impact immune responses to AAV, Bing et al. deployed our NeoScreen platform to determine the stability of binding of wild-type versus deaminated rAAV capsid epitopes in a wide range of HLA class I and class II molecules.
The findings revealed that in some cases deamidation increased stability whereas in other cases it decreased or abrogated stability. This new experimental binding data indicates that epitope deamidation can increase or decrease T cell activation depending on which residues are deamidated, and highlights the need to study not only cytotoxic T lymphocyte responses but also CD4 T cell helper-specific responses in rAAV – based clinical studies.
AAV deamidation impacts T cell epitope binding and cytokine secretion.