Wawrzynski, James Richard; (2025) Molecular treatments for paediatric vitreoretinal disease: developing gene therapy for NDP-related retinal disease and delivering enzyme replacement for CLN2 retinopathy. Doctoral thesis (Ph.D), UCL (University College London).

Text Wawrzynski Thesis.pdf - Accepted Version Access restricted to UCL open access staff until 1 March 2026. Download (159MB)

Abstract

Inherited vitreoretinal disease is a common cause of childhood visual impairment. With the notable exception of treatment for RPE65, no molecular treatments for these conditions are available. I aimed to develop and test a gene therapy for NDP-related retinal disease and to translate a previously studied enzyme replacement therapy for CLN2 retinopathy from animal studies into a human trial. Pathogenic variants in NDP (Xp11.3) result in a spectrum of retinal disease ranging from peripheral non-perfusion to sight-threatening exudative/tractional retinal detachment. In a systematic review of published case reports variants affecting the NDP/FZD4 interaction or the NDP homodimer were found to cause severe disease (historically termed Norrie disease) whereas variants affecting the NDP/LRP5 interaction tended to cause moderate disease (historically termed FEVR). An association between heterozygous NDP pathogenic variants and Coats disease and between otherwise benign variants (in children born at term) in NDP and retinopathy of prematurity was also found. An AAV gene therapy was developed for NDP retinal disease and iterations of the treatment were tested in an Ndp KO mouse model. When administered during retinal vascular development, AAV.NDP rescued vascular architecture, vascular exudation, and the electronegative ERG. When administered later, AAV.NDP reduced exudation and pathological neovascularisation but did not ameliorate the vascular architecture and only partially rescued the ERG. Pathogenic variants in CLN2 result in dysfunctional TPP1 lysosomal enzyme. From the age of 2-4 patients develop progressive neurological decline and retinal dystrophy, followed by premature death. Whilst intracerebroventricular enzyme replacement is available to prevent neurological decline, no treatment is available for the retinopathy. I translated experimental results from a canine model into human patients and found that intravitreal replacement of TPP1 slows CLN2 related retinal degeneration. In summary, this thesis describes the development of an effective novel gene therapy for NDP retinopathy using a murine model and the translation of an enzyme replacement therapy from a canine model into human patients for the first time.

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