Developing Drug and Gene Therapies for Peroxisome Biogenesis Disorders of the Zellweger Spectrum

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Developing Drug and Gene Therapies for Peroxisome Biogenesis Disorders of the Zellweger Spectrum Developing drug and gene therapies for peroxisome biogenesis disorders of the Zellweger Spectrum Catherine Argyriou Department of Human Genetics McGill University, Montréal, Canada June 2018 A thesis submitted to McGill University in partial fulfillment of the requirements of the degree of Doctor of Philosophy © Catherine Argyriou 2018 ABSTRACT Zellweger spectrum disorder (ZSD) usually results from biallelic mutations in PEX genes required for peroxisome biogenesis. PEX1-G843D is a common hypomorphic allele associated with milder disease. We previously showed that fibroblasts from patients with a PEX1-G843D allele recovered peroxisome functions when cultured with the nonspecific chaperone betaine and flavonoid acacetin diacetate. To identify more effective flavonoids for preclinical trials, we compared 54 flavonoids using our cell-based peroxisomal assays. Diosmetin showed the most promising combination of potency and efficacy; co-treatments of diosmetin and betaine showed the most robust additive effects. This was confirmed by 5 independent assays in primary PEX1-G843D patient cells. Neither agent was active in PEX1 null cells. I propose that diosmetin acts as a pharmacological chaperone to improve stability, conformation, and function of PEX1/PEX6 exportomer complexes. All individuals with a PEX1-G843D allele develop a retinopathy that progresses to blindness. To investigate pathophysiology and identify endpoints for experimental trials, I used the knock-in mouse model for the equivalent human mutation, PEX1-G844D. I characterized the progression of retinopathy and found reduced cone cell function and number early in life with more gradual deterioration of rod cell function. Electron microscopy at later stage retinopathy showed disorganization of photoreceptor inner segments and enlarged mitochondria. As retino-cortical function was relatively well-preserved, I propose that the vision defect in the Pex1-G844D mouse is primarily at the retinal level. In contrast to the human PEX1-G843D which behaves as a misfolded, degraded protein in fibroblasts, I found equivalent amounts of murine Pex1-G844D and wild-type Pex1 proteins in retina and other tissues. I propose that murine PEX1-G844D is stable but subfunctional. To determine if we could slow visual loss in PEX1-mediated ZSD, I performed a proof-of-concept trial for PEX1 retinal gene augmentation therapy using the PEX1-G844D mouse. Subretinal injections of AAV-PEX1 at both early and later disease stages resulted in a non-statistically significant trend of improved visual acuity after 2 months, and a twofold improvement in both rod- and cone-mediated retinal electrophysiological response after 5-6 months. Neither injection, viral capsid exposure nor the transgenic protein negatively altered retinal histology or visual response. These results support the potential of retinal gene augmentation to improve vision in patients with ZSD at both earlier and later stages of disease. ii RÉSUMÉ Le Trouble de la biogénèse des peroxysomes du spectre de Zellweger (ZSD) est généralement causé par des mutations bialléliques dans les gènes PEX, qui sont requis pour la biogénèse des peroxysomes. L’allèle hypomorphe PEX1-G843D est le plus fréquent et est associé à une présentation plus légère de la maladie. Nous avons démontré précédemment que les fibroblastes provenant de patients avec un allèle PEX1-G843D récupèrent leurs fonctions peroxysomales lorsque le chaperon non-spécifique bétaïne et le flavonoïde diacétate d’acacétine sont ajoutés à la culture. Dans le but d’identifier les flavoinoïdes les plus efficaces pour des essais pré-cliniques, nous avons comparé 54 flavonoïdes en utilisant des tests cellulaires de la fonction peroxysomale. La combinaison de puissance et d’efficacité la plus prometteuse a été attribuée à la diosmétine; le co-traitement avec la diosmétine et le bétaïne a eu l’effet additif le plus robuste. Cela a été confirmé par 5 tests indépendants dans les cellules primaires PEX1-G843D provenant de patients. Aucun de ces agents n’a été actif dans les cellules nulles pour PEX1. Je propose que la diosmétine agisse comme un chaperon pharmacologique pour améliorer la stabilité, la conformation et la fonction des complexes d’exportation PEX1/PEX6. Toutes les personnes atteintes de ZSD qui ont un allèle PEX1-G843D développent une rétinopathie qui progresse jusqu’à la cécité. J’ai utilisé un modèle de souris knock-in avec la mutation PEX1- G844D, équivalente à la mutation chez les humains, dans le but d’investiguer sur la physiopathologie et d’identifier des paramètres cliniques à mesurer pour les essais expérimentaux. J’ai caractérisé la progression de la rétinopathie et démontré une diminution de la fonction et du nombre de cônes tôt dans la vie des souris, avec une détérioration plus graduelle de la fonction des bâtonnets. L’imagerie à microscope électronique à un stade plus avancé de la rétinopathie a démontré une désorganisation des segments intérieurs des photorécepteurs et des mitochondries élargies. Puisque la fonction rétino- corticale était relativement bien préservée, je propose que la défectuosité de la vision chez les souris PEX1-G844D se situe d’abord au niveau de la rétine. Alors que la protéine PEX1-G843D humaine se comporte comme une protéine mal repliée qui est dégradée dans les fibroblastes, j’ai découvert qu’il y a des quantités similaires de protéines PEX1-G844D et de Pex1de type sauvage dans la rétine et d’autres tissus chez la souris. Je propose donc que le Pex1-G844D chez la souris est stable, mais moins fonctionnelle. Pour déterminer si on peut ralentir la perte de vision chez les personnes atteintes de ZSD dû à un défaut du gène PEX1, j’ai réalisé un essai de preuve de concept pour une thérapie d’augmentation du gène PEX1 dans la rétine des souris PEX1-G844D. Des injections sous-rétiniennes de l’AAV-PEX1 aux stades précoces et avancés de la maladie ont entraîné tendance vers une amélioration de l’acuité visuelle, sans être statistiquement significatives. De plus, cela a permis de doubler les réponses iii électrophysiologiques de la rétine après 5-6 mois. Ni l’injection, ni l’exposition à la capside virale ou la protéine transgénique n’a négativement altéré l’histologie de la rétine ou la réponse visuelle. Ces résultats démontrent le potentiel d’une augmentation génique rétinienne pour améliorer la vision chez les patients atteints de ZSD, aux stades précoce et avancé de la maladie. iv TABLE OF CONTENTS ABSTRACT ........................................................................................................................................... ii RÉSUMÉ .............................................................................................................................................. iii LIST OF ABBREVIATIONS ............................................................................................................... 6 LIST OF FIGURES ............................................................................................................................... 8 LIST OF TABLES ................................................................................................................................. 9 ACKNOWLEDGEMENTS ................................................................................................................ 10 PREFACE TO THE THESIS ............................................................................................................. 11 CONTRIBUTION OF AUTHORS .................................................................................................... 12 CHAPTER I: INTRODUCTION AND LITERATURE REVIEW ................................................ 13 1.1 OVERVIEW AND STUDY RATIONALE ............................................................................ 14 1.2 PEROXISOME BIOLOGY AND CLINICAL DISORDERS ................................................ 15 1.2.1 Peroxisome biochemistry ................................................................................................. 15 1.2.2 Peroxisome biogenesis ..................................................................................................... 18 1.2.3 Clinical disorders ............................................................................................................. 22 1.2.3.1 Zellweger Spectrum Disorder (ZSD) .............................................................................. 24 1.2.3.2 Atypical ZSD presentations ............................................................................................ 26 1.2.3.3 Other disorders that affect peroxisome biogenesis ......................................................... 28 1.2.4 Clinical diagnosis ............................................................................................................. 28 1.2.5 Disease management ........................................................................................................ 29 1.3 MOUSE MODELS OF PBD-ZSD .......................................................................................... 31 1.4 THE MOUSE VISUAL SYSTEM AND ITS ASSESSMENT .............................................. 32 1.4.1 The mouse visual pathway ............................................................................................... 33 1.4.2 Assessing visual function in the laboratory mouse .......................................................... 34 1.4.2.1 Electrophysiology ........................................................................................................... 35 1.4.2.2 Visual acuity
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