A Fixed-Depth Microneedle Enhances Reproducibility and Safety for Corneal Gene Therapy. Issue 3 (March 2020)

• Record Type: Journal Article
• Authors: Gilger, Brian C.; Crabtree, Elizabeth; Song, Liujiang; Llanga, Telmo; Cullen, Megan; Blanchard, Allison; Salmon, Jacklyn; Patel, Samirkumar; Zarnitsyn, Vladimir; Hirsch, Matthew
• Is Part Of: Cornea. Volume 39:Issue 3(2020)
• Publication Date: 2020-03
• Subjects: cornea -- stromal -- gene therapy -- safety; Cornea -- Periodicals; Cornea -- Periodicals; Cornée -- Périodiques; 617.719
• DOI: 10.1097/ICO.0000000000002182
• Languages: English
• ISSNs: 0277-3740

Abstract

Abstract : Purpose: Drug delivery directly to the corneal stroma currently relies on microscopic injections that demonstrate low reproducibility and clinician-dependent variability. With use of biological drugs such as adeno-associated viral (AAV) vectors, precise and consistent drug deposition is critical to reduce concerns related to off-target transduction and the host's immune response to the viral capsid and/or transgene-derived product. Therefore, a precise corneal injection (PCI) microneedle was designed to allow accurate depth-specific injections into the corneal stroma in a macroscopic setting. Methods: High-frequency ultrasound and confocal microscopy demonstrated the consistent ability to predetermine the precise injection depth using PCI needles of varying sizes. Next, a comparison between a standard 31-G needle and PCI needles was performed in vivo using AAV vector gene delivery. Results: Intrastromal corneal injections using the PCI microneedle resulted in less vector leakage at the site of injection and fewer anterior chamber penetrations compared with a standard 31-G needle. Although reporter gene expression appeared similar when the vector was administered with either needle type, a trend toward increased vector genomes was noted in the PCI-injected corneas at the experimental conclusion. As hypothesized, corneal perforation resulted in increased detection of AAV vector genomes in nontarget tissues, highlighting the importance of consistency for biological drug applications in the cornea. Conclusions: Further development of the PCI microneedle is warranted especially for AAV corneal gene therapy and offers the potential to enhance transduction while significantly reducing safety concerns and intraclinician and interclinician injection variability. Abstract : Supplemental Digital Content is Available in the Text.