Antonia W. Godehardt

Review on porcine endogenous retrovirus detection assays—impact on quality and safety of xenotransplants

Xenotransplantation of porcine organs, tissues, and cells inherits a risk for xenozoonotic infections. Viable tissues and cells intended for transplantation have to be considered as potentially contaminated non‐sterile products. The demands on microbial testing, based on the regulatory requirements, are often challenging due to a restricted shelf life or the complexity of the product itself. In Europe, the regulatory framework for xenogeneic cell therapy is based on the advanced therapy medicinal products (ATMP) regulation (2007), the EMA CHMP Guideline on xenogeneic cell‐based medicinal products (2009), as well as the WHO and Council of Europe recommendations. In the USA, FDA guidance for industry (2003) regulates the use of xenotransplants. To comply with the regulations, validated test methods need to be established that reveal the microbial status of a transplant within its given shelf life, complemented by strictly defined action alert limits and supported by breeding in specific pathogen‐free (SPF) facilities. In this review, we focus on assays for the detection of the porcine endogenous retroviruses PERV‐A/‐B/‐C, which exhibit highly polymorphic proviral loci in pig genomes. PERVs are transmitted vertically and cannot be completely eliminated by breeding or gene knock out technology. PERVs entail a public health concern that will persist even if no evidence of PERV infection of xenotransplant recipients in vivo has been revealed yet. Nevertheless, infectious risks must be minimized by full assessment of pigs as donors by combining different molecular screening assays for sensitive and specific detection as well as a functional analysis of the infectivity of PERV including an adequate monitoring of recipients.

Comparative gene expression profiling of pig-derived iPSC-like cells: Effects of induced pluripotency on expression of porcine endogenous retrovirus (PERV)

Porcine induced pluripotent stem cells (piPSCs) offer an alternative strategy in xenotransplantation (XTx). As human endogenous retroviruses (HERV), particularly HERV‐K, are highly expressed in natural human stem cells, we compared the expression of porcine endogenous retroviruses (PERV) and retrotransposon LINE‐1 (L1) open reading frames 1 and 2 (pORF1 and pORF2) in different piPSC‐like cell lines with their progenitors (porcine fetal fibroblasts, pFF).

Genehmigungsverfahren für klassische Gewebezubereitungen gemäß § 21a Arzneimittelgesetz (AMG)

Am 1. August 2007 trat in Deutschland das Gewebegesetz in Kraft, welches unter anderem Regelungen hinsichtlich der Qualität und Sicherheit von Gewebezubereitungen (GWZ) trifft. Klassische GWZ sind Arzneimittel für die Anwendung am Menschen, a) die menschliche Gewebe und Zellen enthalten oder ausgehend von diesen hergestellt werden, b) deren wesentliche Be- oder Verarbeitungsverfahren in der EU hinreichend bekannt bzw. neu, aber mit bekannten Verfahren vergleichbar sind, und c) deren Wirkungen und Nebenwirkungen aus dem wissenschaftlichen Erkenntnismaterial ersichtlich sind. Dazu gehören z.B. Herzklappen, Corneae, muskuloskelettale GWZ, Gefäße oder Stammzellen aus Knochenmark. Wenn bei einer GWZ die oben genannten Voraussetzungen erfüllt sind und diese nicht mit ionisierenden Strahlen behandelt wird, ist für das Inverkehrbringen eine Genehmigung gemäß § 21a Abs. 1 Arzneimittelgesetz (AMG) durch das Paul-Ehrlich-Institut erforderlich. Zur Erleichterung der Antragstellung für die Genehmigung stehen Formulare auf der Internetseite des Paul-Ehrlich-Instituts zur Verfügung. Schwerwiegende unerwünschte Reaktionen und schwerwiegende Zwischenfälle gemäß § 63c AMG müssen von Gewebeeinrichtungen unverzüglich an die zuständige Bundesbehörde gemeldet werden. Des Weiteren besteht für Gewebeeinrichtungen eine Meldepflicht gemäß § 8d Abs. 3 Transplantationsgesetz (TPG) zur Erfassung der verarbeiteten Gewebe, die in Form eines jährlichen Berichts bis zum 1. März des folgenden Jahres an das Paul-Ehrlich-Institut erfolgt.

Xenogene Zelltherapeutika@@@Xenogeneic cell therapeutics: Behandlung von Typ 1 Diabetes mittels porciner Pankreasinseln und -inselzellen@@@Treatment of type 1 diabetes using porcine pancreatic islets and islet cells

In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.

Xenogene ZelltherapeutikaXenogeneic cell therapeutics

In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.

[Xenogeneic cell therapeutics: Treatment of type 1 diabetes using porcine pancreatic islets and islet cells].

In view of the existing shortage of human donor organs and tissues, xenogeneic cell therapeutics (xCT) offer an alternative for adequate treatment. In particular, porcine pancreatic islets and islet cells have already entered the field of experimental therapy for type-1 diabetes mellitus (T1DM) patients. Thereby, xCT depict challenging products with a glance on medical, ethical, and regulatory questions. With cross-species transplantation (xenotransplantation), the risk of immunological graft rejection as well as the risk of infectious transmission of microbial and viral pathogens must be considered. This includes the bidirectional transmission of microorganisms from graft to host as well as from host to graft. Crossing the border of species requires a critical risk-benefit evaluation as well as a thorough longtime surveillance of transplant recipients after treatment. The international legal and regulatory requirements for xCT are inter alia based on the World Health Organization criteria summarized in the Changsha Communiqué (2008). In the European Union, they were reflected by the European Medicines Agency (EMA) Guideline on Xenogeneic Cell-based Medicinal Products following the implementation of the Regulation on Advanced Therapies (ATMP). On the basis of this regulation, the first non-clinical and clinical experiences were obtained for porcine islets. The results suggest that supportive treatment of T1DM risk patients with xCT may be an alternative to established allogeneic organ transplantation in the future.