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Information to Users INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, sorne thesis and dissertation copies are in tyPewriter face, while others may be tram any type of comPUter printer. Th. qu.11ty of thla reproduction la dependent upon the quallty of th. capy submltted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough. substandard margins, and improper alignment can adversely affect reproduction. ln the unlikely event that the author did not send UMI a complete manuscript and there are missing pages. these will be noted. Also. if unauthorized copyright material had ta be removect, a note will indicate the deletion. Oversize materials (e.g., maps, drawings, charts) are reproduced by S8Ctioning the original, beginning at the upper left·hand corner and cantinuing from left to right in equal sections with smaU overlaps. ProQuest Information and Leaming 300 North Zeeb Raad. Ann Arbor. MI 48106-1346 USA 800-521-0600 • Enzyme substitution tberapy for hyperphenylalaninemia with phenylalanine ammonia Iyase. An alternative to low phenylalanine dietary treatment; effective in mouse models. By Cbristineh N. Sarkissian Depanment of Biology McGill University, Montreal November 2000 A thesis submitted to the Faculty ofGraduale Studies and Research in partial fulfillment of the requirements of the degree of Doctor of Pbüosophy @ Cbristineb N. Sarkissian (2000) • National LInIy I~I dCaMda =:::::rllïces 311 "''''''1111" 8tre.t a.-ON K1AON' CIMdI The autbor bas granted a DOD­ L'auteur a accordé une licence non exclusive licence aIlowiDg the exclusive permeuaat à la Natioual Lihrary ofCanada to Bibüothèque Datiouale du Canada de reproduce, 1081l, distnbute or sen reproduire, pdter, distnbuer ou copies oftbis tbesis in microfOl'lD, YeDdre des copies de cette thèse sous pape!' or electronic formats. la forme de microfiche/film, de reproduction sur papier ou sur fonDat électrODique. The autbor retaiDs ownersbip ofthe L'auteur conserve la propriété du copyright intbis thesïs. Neidathe droit d'auteur qui protège cette thèse. thesis DOt substantiaJ extracts ftom it Ni la thèse Di des eXbaits substantiels may be printed or otherwise de cene-ci ne doivent être imprimés reproduced witbout the author's ou autrement reproduits saDS son permission. autorisation. 0-612-70148-4 • To Mum and Dad who gave up ail Iheir comfons and moved Ihree continents, 10 provide us wilh every opponunity to be ail lha! we wanted 10 be. • • TABLE OF CONTENTS TABLE OF CONTENTS 1 ABSTRACT IV RÉSUMÉ VI ABBREVIATIONS VIn LIST OF TABLES AND ftGURES X PREFACE XIII ACKNOWLEDGEMENTS XV CONTRIBUTIONS OF AUTHORS XIX CIIAPI'ER 1: introduction 1 Discovery of PKU 2 Defining Hyperphenylalaninemia 2 The Phenylalanine Hydroxylase Gene 3 Mutations Associated with PAH Deficiency 4 PAR Expression S The PAH Polypeptide and Enzyme 6 Phenylalanine Homeostasis 8 Treatment Outeome 9 Brain Pathogenesis 10 The Challenge of Maternai HPA 13 Relevance of Animal Models 14 Phenylalanine Transamioation Metabolites 19 Treatment 21 Treatment Difficu1ties and Otber Associated Drawbacks 23 Non-Diet TreabDent Options 26 Treatment by Liver Transplants 26 Gene Therapy 26 Tetrahydrobiopterin-Responsive HPA Therapy 27 Enzyme Therapy 28 PAR Enzyme Replaœment 28 Enzyme Substitution Therapy wim 28 Phenylalanine Ammonia Lyase Route of PAL Administntion 30 ProposaI 33 References 37 CONNECI1NG TEXT 66 • 1 CIIAPI'ER 2: A heteroaUeUe mutant mouse model: A new 67 orthologue for human hyperphenylalanlnemia • Abstract 68 Introduction 69 Materials and Methods 70 Results 74 Discussion 76 Acknowledgements 77 References 85 CONNECTING TEXT 89 CIIAPI'ER 3: Measurement of phenyUactate, pheaylaeetate and 90 phenylpyruvate by negative ion cbemical ionizadon - lU chromatography/mass spedrometry in brain of mouse genette models of pheoylketonuria and non- pbenylketODuria hyperphenyl8181Jinemia Abstract 91 Introduction 92 Materials and Methods 93 Results and Discussion 96 Acknowledgements 99 References 109 CONNECTING TEXT 111 CBAPTER 4: A dUferent approach to treatment of phenylketonuria: 112 Phenylalanine degnulation with recombinant phenylalanine ammoaia lyase Abstract 113 Introduction 114 Materials and Methods 115 Results 121 Discussion 122 Acknowledgements 125 References 133 CIIAPI'ER 5: Discussion 139 The Heteroallelic Mouse 140 Metabolic Manipulation 142 Pah Enzyme Activity 142 PAR Enzyme Stability 143 Measuring Bebavior 144 • 0 Reproductive Problems 144 Phenylalanine Metabolites 145 • Logic and Role of Low Phenylalanine Diet 147 PAL Protection and Use as an Alternative to Diet Therapy 148 Future Aims 152 References 154 CLAIMS TO ORIGINALITY 162 APPENDIXA 165 APPENDIXB 173 APPENDIXC 182 APPENDIXD 189 APPENDIXE 193 • m ABSTRACT • Phenylketonuria (PKU) and related forms of oon-PKU hyperphenylalaninemias (HPA) result from deficiencies in phenylalanine hydroxylase (PAH), the hepatic enzyme that catalyses the conversion of phenylalanine (phe) to tyrosine (tyr). Patients are cbaracterised by a metabolic phenotype comprising elevated levels of phe and some of its Metabolites, notably phenyUactate (pLA), phenylacetate (PAA) and phenylpynavate (PPA), in both tissue and body fluids. Treatment from binh witb low-phe diet largely prevents the severe mental retardation that is its major consequence. Mecbanisms underlying the patbophysiology of PKU are still Dot fully understood; to this end, the availability of an onbologous animal model is relevant. A number of N-ethyl-N-nitrosourea (ENV) mutagenized mouse strains bave become available. 1 repon a new heteoraUelic strain, developed by crossing female ENUI (with mUd non-PKU HPA) with a male ENU2/ + carrier ofa 'severe' PKU-causing allele. 1 descnlJe the new bybrid ENUl/2 strain and compare it witb control (BTBRIPas), ENUl, ENU2 and the beterozygous counterparts. The ENUl, ENUl/2 and ENU2 strains display mild, moderate and severe phenotypes, respectively, relative to the control and beterozygous counterparts. 1 descnlJe a DOvel merbod using negative ion chemical ionization gas chromatography/mass spectrometry (NICI-GC/MS) to measure the concentration of PLA, PAA and PPA in the brain of normal and mutant mice. Although elevated moderately in HPA and more 50 in PKU mice, concentrations of these Metabolites are not sufficient to explain impaired brain function; however phe is present in brain al levels associated with barm. Finally, 1 describe a new modality for treatment of HPA, compatible with better human compliance: it involves enzyme substibltion wim non-absorbable 8Dd proteeted phenylalanine ammonia Iyase (PAL) in the intestiDal lumen, to conven L-phenylalanine ta the barmless metabolites (trans-einnamic acid and trace • IV ammonia). PAL, taken orally, substitutes for the deficient PAR enzyme and • depletes body pools of excess phe. 1 describe an efficient recombinant approach to produce PAL enzyme. 1 also provide proofs of both pharmacologic and physiologic principles by testing PAL in the onhologous mutant mouse strains with HPA. The till(lings encourage further development of PAL for oral use as an ancillary treabDent ofhumao PKU. • v RÉSUMÉ • La phénylcétonurie (PCU) et autres formes d'hyperphénylalaninémies (HPA) résultent du malfonctionnement de la pbénylalanine hydroxylase (PAH), l'enzyme bépatique catalysant la conversion de la pbénylalanine (phe) en tyrosine (tyr). Les patients atteints de PeU présentent dans leurs tissues et leurs liquides corporels des niveaux élevés de pbe et certains métabolites, notamment la phényUactate (PLA), la phénylacétate (PAA) et la pbénylpyruvate (PPA). Une diète (à la naissance) à faible teneur en pbe prévient grandement le retard mental sévère, caractéristique de la PCU. Les mécanismes impliqués dans la physiopathologie ne sont pas entièrement compris; c'est pourquoi un modèle animal onhologue est nécessaire. fi existe les soucbes de souris ENUI (avec légère HPA) et ENU2 (avec PCU) obtenues par mutation induite à la N-etbyl-N-nitrourée (ENU). Je décris maintenant une nouveUe souche bétéroallélique, ENUl/2 (ENU19 x ENU21 +0), et compare cette souche avec les contrôles (BTBRIPas), ENUl, ENU2 et leurs hétérozygotes respectifs. Les phénotypes sont: ENUI Oéger), ENUl/2 (modéré), ENU2 (sévère), lorsque comparé aux con~les et bétérozygotes. Je décris une nouvelle méthode utilisant la chromatographie gazeuse d'ionisation chimique d'ions négatifs couplée à la spectrométrie de masse (NICI­ GCIMS) pour mesurer la concentration de PLA, PAA et PPA dans le cerveau de souris. Même si les niveaux sont élevés dans la souris HPA Oégèrement) et PeU (beaucoup), la concentration de ces métabolites est insuffisante pour expliquer le malfonctionnement du cerveau. Cependant, la quantité de pbe est suffisante pour causer certains dommages. Finalement, je décris un nouveau mode de traitement de HPA qui est compatible avec un usage chez l'humain. Ceci implique la substitution d'enzyme avec la Iyase phenylalanine ammoniaque (LPA) protégée (non-absorbable) dans le lumen intestinale. Ceci permet de convenir la L-pbenylalanine en métabolites • VI inoffensifs (l'acide trans-cjnnamique et des traces d'ammoniaque). La LPA, prise • oralement, peut se substituer à l'enzyme déficiente PAH et éliminer l'excès de phe corporel. Je décris une approche recombinante efficace pour produire l'enzyme PAL. Aussi, je fournis des preuves aux niveaux pharmacologique et physiologique en testant PAL chez les souches de souris mutantes orthologues avec HPA. Ces découvenes
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