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RIVM Reprot 320001001 Effect of Administration Route On Report 320001001/2008 E.F.A. Brandon | B. Tiesjema | J.C.H. van Eijkeren | H.P.H. Hermsen Effect of administration route on biodistribution and shedding of replication-deficient viral vectors used in gene therapy A literature study RIVM Report 320001001/2008 Effect of administration route on biodistribution and shedding of replication-deficient viral vectors used in gene therapy A literature study E.F.A. Brandon B. Tiesjema J.C.H. van Eijkeren H.P.H. Hermsen Contact: E.F.A. Brandon Centre for Substances and Integrated Risk Assessment [email protected] This investigation has been performed by order and for the account of Office for Genetically Modified Organisms of the National Institute for Public Health and the Environment RIVM, P.O. Box 1, 3720 BA Bilthoven, telephone: +31 – 30 – 274 91 11; telefax: +31 – 30 – 274 29 71 © RIVM 2008 Parts of this publication may be reproduced, provided acknowledgement is given to the 'National Institute for Public Health and the Environment', along with the title and year of publication. 2 RIVM report 320001001 Abstract Effect of administration route on biodistribution and shedding of replication-deficient viral vectors used in gene therapy A literature study In gene therapy, genes (heredity material) are introduced in patients to treat diseases caused by deletions or alterations in genes. With adapted viruses it is possible to direct the gene of interest to a desired place in the body. This modified virus is called a viral vector. The gene of interest can also spread, via the viral vector, to a site outside the patient. The gene can then possibly be transferred to other people, animals and other organisms where it may cause undesired effects. To evaluate the risks of viral spreading, knowledge of how the viral vector behaves inside the body and subsequently leaves it, for example via faeces, urine or saliva, is crucial. In this report, the distribution in and the excretion from the body of two viral vectors (HAdV-5 and AAV2) per administration route (i.e. via blood or muscles) have been critically evaluated. It can be concluded that as well as the type of viral vector involved, the administration route also influences the distribution and excretion of the viral vector. The viral vector remains local through some routes and is then only excreted via only one or a few routes. Other routes result in distribution throughout the entire body and excretion via several routes. These processes are described in qualitative models. The information from these models is relevant for researchers, risk assessors and regulators in the development of viral vectors for gene therapy. Key words: viral vectors, gene therapy, shedding, biodistribution, HAdV-5, AAV2 RIVM report 320001001 3 4 RIVM report 320001001 Rapport in het kort Effect van de toedieningsroute op de biodistributie en excretie van replicatie-deficiënte virale vectoren welke gebruikt worden bij gentherapie Een literatuur studie Bij gentherapie worden genen (erfelijk materiaal) bij patiënten ingebracht om ziektes te behandelen waarvan de oorzaak een ontbrekend of veranderd gen is. Met aangepaste virussen is het mogelijk om het te introduceren gen naar de gewenste plek in het lichaam te brengen. Dit veranderde virus wordt een virale vector genoemd. Het te introduceren gen kan zich via de virale vectoren ook buiten de patiënt verspreiden. Dat kan zowel in mensen, als in dieren en andere organismen, waar het eventueel ongewenste effecten kan veroorzaken. Om de risico’s van verspreiding te beoordelen is kennis nodig over de manier waarop het virus zich binnen het lichaam gedraagt en over hoe het vervolgens het lichaam verlaat, via bijvoorbeeld ontlasting, urine of speeksel. In dit rapport wordt van twee virale vectoren (HAdV-5 en AAV2) per toedieningsroute, via bijvoorbeeld het bloed of de spieren, kritisch geëvalueerd hoe zij zich in het lichaam verspreiden en hoe zij zich uitscheiden. Het blijkt dat behalve het type virale vector, de toedieningsroute invloed heeft op de verdeling en uitscheiding van de vector. Via sommige toedieningsroutes blijft de virale vector lokaal en wordt hij via één of enkele routes uitgescheiden. Andere toedieningsroutes resulteren in verspreiding over het hele lichaam en uitscheiding via meerdere routes. Deze processen zijn beschreven in kwalitatieve modellen. De informatie uit deze modellen is relevant voor onderzoekers, risicobeoordelaars en het beleid bij de ontwikkeling van virale vectoren voor gentherapie. Trefwoorden: virale vectoren, gentherapie, uitscheiding, biodistributie, HAdV-5, AAV2 RIVM report 320001001 5 6 RIVM report 320001001 Contents ABBREVIATIONS.......................................................................................................................................11 SUMMARY ...................................................................................................................................................13 1 INTRODUCTION ................................................................................................................................15 1.1 GENE THERAPY ...............................................................................................................................15 1.2 GOAL ..............................................................................................................................................15 1.3 ADENOVIRUS (AD)..........................................................................................................................16 1.3.1 Wild type virus .......................................................................................................................16 1.3.2 Attachment and entry of adenoviral vectors ..........................................................................16 1.4 ADENO-ASSOCIATED VIRUS (AAV) ................................................................................................17 1.4.1 Wild type virus .......................................................................................................................17 1.4.2 Attachment and entry of AAV vectors ....................................................................................17 1.5 QUANTITATIVE MODELLING............................................................................................................18 2 METHOD..............................................................................................................................................21 3 RESULTS..............................................................................................................................................23 3.1 ANALYSIS .......................................................................................................................................23 3.1.1 Viral titres..............................................................................................................................23 3.1.2 Assays ....................................................................................................................................23 3.1.3 Administration route ..............................................................................................................24 3.2 RESULTS HADV-5 ..........................................................................................................................24 3.2.1 Biodistribution and shedding per administration route.........................................................26 3.2.1.1 Intravenous administration ............................................................................................................... 26 3.2.1.2 Intraperitoneal and intra-pleural administration................................................................................26 3.2.1.3 Intra-tumoral administration............................................................................................................. 26 3.2.1.4 Dermal administration ...................................................................................................................... 27 3.2.1.5 Intra-prostatic administration............................................................................................................ 27 3.2.1.6 Brain administration ......................................................................................................................... 27 3.2.1.7 Intra-muscular administration........................................................................................................... 28 3.2.1.8 Inhalatory and intranasal-bronchial administration........................................................................... 28 3.2.1.9 Administration via other routes ........................................................................................................ 28 3.2.2 Shedding per excretion route .................................................................................................29 3.2.2.1 Urine................................................................................................................................................. 29 3.2.2.2 Faeces ............................................................................................................................................... 30 3.2.2.3 Mouth and nose secreta..................................................................................................................... 30 3.2.2.4 Semen ..............................................................................................................................................
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