Author: M Dominik Fischer (United Kingdom)
Co-authors: Karl Ulrich Bartz-Schmidt, Spyridon Dimopoulos, Claudio Spera
Voretigene neparvovec (VN) is the first ocular gene therapy approved in the United States and the European Union for the treatment of patients with visual impairment due to confirmed biallelic RPE65 mutation-associated inherited retinal dystrophy (IRD). The surgical technique for administration of VN in clinical practice at the University Eye Hospital (UEH) Tübingen in Germany is outlined herein, and the most common pitfalls that may occur during subretinal bleb formation are outlined. Furthermore, we provide guidance on measures that can be taken to successfully mitigate such hurdles.
Subretinal injection of VN at UEH Tübingen, Centre for Ophthalmology in Germany, for the treatment of patients with visual impairment due to confirmed biallelic RPE65 mutation-associated IRD.
An immunomodulatory regimen is initiated three days before the scheduled surgical procedure. On the day of surgery, after the patient has been cleared for surgery by the anesthesiologist, the pharmacy collects the VN vial from freezer storage (≤-65°C), and prepares the drug. The VN administration procedure begins within 4 hours from when the drug is thawed by the pharmacy. Prior to the subretinal injection, a 3-port Pars Plana Vitrectomy is performed and a posterior vitreous detachment is induced. The injection site should be located along the retinal superior vascular arcade and should not be located within areas that have pathological features. With the initiation of the bleb, a total of 300μl of VN is slowly injected into the subretinal space. After subretinal injection, a retinal examination is carried out to evaluate for retinal abnormalities that would require further management. A fluid-air exchange is then performed to remove any excess gene therapy vector in the vitreous cavity and to provide tamponade. Following surgery, the patient is closely monitored and the corticosteroid regimen is continued for up to 14 days. Surgical cases were reviewed to depict the most common hurdles that may occur in subretinal bleb formation.
Employing the surgical technique described above, nine patients between 14 and 36 years of age, and with sufficient viable retinal cells, received VN treatment at UEH Tübingen following biallelic RPE65 mutation-associated retinal dystrophy diagnosis. Three subjects received subretinal injections of 300μl of VN in the contralateral eye, after initial unilateral injection. On review of the 12 surgeries performed to date, the most common hurdle that may occur in subretinal bleb formation include i) the dissemination of vector suspension into the vitreous without bleb formation, ii) sudden influx of air bubbles into the bleb and iii) a bleb that does not cover the target area. Mitigation strategies include i) the use of intra-operative optical coherence tomography (OCT), ii) priming of the injection system just prior to insertion of needle through trocar and iii) placement of retinotomies just inside the main vascular arcade. A bleb was successfully raised and VN administered in each case, with treated patients closely monitored following surgery. Follow-up examinations included OCT and fundus autofluorescence imaging in order to assess post-surgical outcomes.
The patient journey and VN administration procedure at UEH Tübingen is dependent on timely, efficient, concise communication between the multidisciplinary team. Using the surgical technique and mitigation strategies described above, and with effective communication between the assistant and lead surgeon, a bleb was raised and 300μl of VN was successfully delivered into the subretinal space in each of the 12 surgeries performed at UEH Tübingen.
M Dominik Fischer reports consulting fees from Adelphi Values, Advent France Biotechnology, Alphasights, Arctos Medical, Atheneum, Axiom Healthcare Strategies, Biogen, Cambridge Consultants, Decision Resources, Dialectica, Frontera Therapeutics, Janssen Research & Development, Navigant, Novartis, Roche, RegenxBio, Sirion, System Analytic, and STZeyetrial. He has no employment at Novartis, no intellectual property rights and/or financial interest in Luxturna; Karl Ulrich Bartz-Schmidt reports grants from Novartis during the conduct of the study; Spyridon Dimopoulos has nothing to disclose; Claudio Spera is an employee of Novartis.