Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY/ABSTRACT Gene therapy has made significant progress in recent years, with FDA approvals for liver and muscle disorders. However, lung-directed gene therapy lags behind due to unique challenges posed by vector tropism and mucosal immune responses. While inhaled gene is being explored in lung disorders such as Cystic Fibrosis (CF), primary ciliary dyskinesia, pulmonary arterial hypertension, and lymphangioleiomyomatosis, clinical trials with AAV-mediated gene delivery have identified two major barriers to successful, long-term gene expression: (1) cross presentation of AAV capsid and elimination of transduced cells by CD8+ cytotoxic T- lymphocytes (CTLs), and (2) potent humoral responses which prevent administration in seropositive individuals by immune responses. These immune responses limit treatment effectiveness in the liver and muscle, but their role in the context of lung-directed gene delivery has not been explored. Our lab has carried out foundational studies investigating the unique mucosal niche where B- (BRM) and T- (TRM) resident memory cells arise in response to local antigen, ready to respond rapidly upon re-exposure. Specifically, we have discovered that B cells, rather than dendritic cell are key antigen-presenting cells (APCs) for fungal antigens in the lung. However, their role in the context of inhaled gene therapy is not known. Based in part that αCD20 has been used in CF lung transplantation and is well tolerated, we investigated αCD20 in the context of lung gene therapy. Our preliminary data indicate αCD20 antibody prior to primary adenoviral vector administration blocks the generation of BRM cells, attenuates activated CD8+ TRM and completely rescues secondary gene transfer. In my preliminary studies, I have identified a critical role for airway immunoglobulins (Igs) in limiting re-dosing with unimpeded secondary adenoviral airway gene transfer occurring despite the formation of serum anti-vector antibodies (in review). In this proposal, we will investigate this strategy for clinically relevant AAV vectors. Based on this, we hypothesize that that lung epithelial tropic AAV6.2 elicits lung CD8+ and B-cell resident memory cells and that administration of αCD20 prior to vector- based gene transfer in the absence of preexisting immunity will attenuate these responses and allow more efficient repeated vector delivery. In Aim 1, we will test the hypothesis that AAV6.2 delivery to the respiratory tract will elicit mucosal resident-memory immune responses that limit redosing. In Aim 2, we will test the hypothesis that αCD20 treatment prior to primary vector delivery to the lung can prevent B- and T-cell responses and permit re-dosing.
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