April 2014
Volume 55, Issue 13
Free
ARVO Annual Meeting Abstract  |   April 2014
Evaluation of an optimised injection system for retinal gene therapy in human patients
Author Affiliations & Notes
  • M Dominik Fischer
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Markus Groppe
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Doron Hickey
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
  • Mandeep S Singh
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Robert E MacLaren
    Nuffield Laboratory of Ophthalmology, University of Oxford, Oxford, United Kingdom
    Oxford Eye Hospital, Oxford University Hospitals NHS Trust, Oxford, United Kingdom
  • Footnotes
    Commercial Relationships M Dominik Fischer, None; Markus Groppe, None; Doron Hickey, None; Mandeep Singh, None; Robert MacLaren, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 6001. doi:
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      M Dominik Fischer, Markus Groppe, Doron Hickey, Mandeep S Singh, Robert E MacLaren; Evaluation of an optimised injection system for retinal gene therapy in human patients. Invest. Ophthalmol. Vis. Sci. 2014;55(13):6001.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose: Increasing numbers of clinical gene therapy trials comprise subretinal injections of viral vector solutions in patients with retinal dystrophies. Structural characteristics of affected retinal tissue therefore have to be taken into account when optimising surgical procedures. We have evaluated a semi-automated injection system used in the choroideremia clinical gene therapy trial NCT01461213 regarding aspects of safety and reproducibility.

Methods: Viral vector solution was produced according to GMP standards with or without 0.001% Pluronic® F-68, drawn up in a 1ml polypropylene syringe with modified plunger cap system. Retinotomy and subretinal injection was achieved through a standard 23G port system for vitrectomy with a Dorc Teflon 41G needle attached to a Luer-Lok 23G needle. Aspiration and injection were controlled via the Accurus® Surgical System for precise regulation of fluid movement.

Results: Use of surfactant Pluronic® F-68 prevented loss of vector particles (vp) in the polypropylene injection system (concentration of vp in ejected solution with PF-68: 1.88e11 ± 3.81e10 vp/ml; without PF-68: 3.19e10 ± 4.14e9 vp/ml; p = 0.004). The Dorc 41G/Luer-Lok 23G system allowed direct visualisation of vector solution to control for air inclusion prior to injection. The digitally controlled infusion system provided superior control for precise, single-handed injection at up to 67 kPa (500 mmHg) aspiration/ejection pressure, showing steady aspiration and ejection of fluid as visualised with a blue dye formulated for intraocular use.

Conclusions: Safe and controlled surgical access to the subretinal space is of paramount importance for safety and efficacy in trials involving the subretinal delivery of experimental compounds such as viral vector or stem cell suspensions. The optimised injection system takes into account small volumes as well as different viscosities (e.g. virion vs. stem cell) and provides safe and controlled infusion into the subretinal space in human patients.

Keywords: 538 gene transfer/gene therapy • 762 vitreoretinal surgery • 688 retina  
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