Update regarding xenotransplantation in Japan

Shimoda, Masayuki; Matsumoto, Shinichi

doi:10.1111/xen.12491

Cited by 11 publications

(10 citation statements)

References 9 publications

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“…Although there had been no reports on human PERV infection in any experimental, pre‐clinical, and clinical trial, 47 the related retrovirus‐like murine leukemia virus, feline leukemia virus, and koala retrovirus have a risk of inducing tumors 47 . To address this risk of PERV infection, U.S Food and Drug Administration (FDA) as well as Japanese regulatory authority published guidelines to minimize PERV infection 48,49 . The important strategy is confirming no transfection using co‐culture test with HEK‐293 cells, transplanting the cells with low copy numbers of PERV A and B, following up the recipients and their close relatives for life‐long and archiving samples for long‐term.…”

Section: Discussionmentioning

confidence: 99%

Xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis

Yamada

Sakata

Nishimura

et al. 2021

Xenotransplantation

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Background The clinical utility of stem cell therapy for peripheral artery disease has not been fully discussed, and one obstacle is limited donor supplies. In this study, we attempted to rescue mouse ischemic hind limb by xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells (npBM‐MSCs). Methods Neonatal porcine bone marrow‐derived mesenchymal stem cells were transplanted to ischemic hind limbs of male C57BL/6J mice (npBM‐MSCs group). Mice with syngeneic transplantation of mouse BM‐MSCs (mBM‐MSCs group) were also prepared for comparison. The angiogenic effects were evaluated by recovery of blood flow on laser Doppler imaging, histologic findings, and genetic and protein levels of angiogenic factors. Results Regarding laser Doppler assessments, blood flow in the hind limb was rapidly recovered in the npBM‐MSCs group, compared with that in the mBM‐MSCs group (P = .016). Compared with the mBM‐MSCs group, the npBM‐MSCs group had early and prominent lymphangiogenesis [P < .05 on both post‐operative days (PODs) 3 and 7] but had similar angiogenesis. Regarding genomic assessments, xenotransplantation of npBM‐MSCs enhanced the expressions of both porcine and murine Vegfc in the hind limbs by POD 3. Interestingly, the level of murine Vegfc expression was significantly higher in the npBM‐MSCs group than in the mBM‐MSCs group on PODs 3 and 7 (P < .001 for both). Furthermore, the secreted VEGFC protein level was higher from npBM‐MSCs than from mBM‐MSCs (P < .001). Conclusion Xenotransplantation of npBM‐MSCs contributed to the improvement of hind limb ischemia by both angiogenesis and lymphangiogenesis, especially promotion of the latter. npBM‐MSCs may provide an alternative to autologous and allogeneic MSCs for stem cell therapy of critical limb ischemia.

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Section: Discussionmentioning

confidence: 99%

Xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis

Yamada

Sakata

Nishimura

et al. 2021

Xenotransplantation

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“…According to the Revised Pharmaceutical Affairs Act effective from 2014, a provisional approval of xenogeneic cells will grant the product a conditional term of 7 years, during which additional efficacy and safety data should be collected. To prevent infections and the spread of emerging infectious diseases caused by xenotransplantation, the Research and Development Division, Health Policy Bureau, MHLW updated and published the “Public Health Guidelines on Infectious Disease Issues in Xenotransplantation” in 2016 ( Shimoda and Matsumoto, 2019 ).…”

Section: Regulatory Framework and Ethical Issues In Xenotransplantatimentioning

confidence: 99%

Corneal xenotransplantation: Where are we standing?

Yoon¹,

Choi²,

Kim

2021

Progress in Retinal and Eye Research

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The search for alternatives to allotransplants is driven by the shortage of corneal donors and is demanding because of the limitations of the alternatives. Indeed, current progress in genetically engineered (GE) pigs, the introduction of gene-editing technology by clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9, and advanced immunosuppressants have made xenotransplantation a possible option for a human trial. Porcine corneal xenotransplantation is considered applicable because the eye is regarded as an immune-privileged site. Furthermore, recent non-human primate studies have shown long-term survival of porcine xenotransplants in keratoplasty. Herein, corneal immune privilege is briefly introduced, and xenogeneic reactions are compared with allogeneic reactions in corneal transplantation. This review describes the current knowledge on special issues of xenotransplantation, xenogeneic rejection mechanisms, current immunosuppressive regimens of corneal xenotransplantation, preclinical efficacy and safety data of corneal xenotransplantation, and updates of the regulatory framework to conduct a clinical trial on corneal xenotransplantation. We also discuss barriers that might prevent xenotransplantation from becoming common practice, such as ethical dilemmas, public concerns on xenotransplantation, and the possible risk of xenozoonosis. Given that the legal definition of decellularized porcine cornea (DPC) lies somewhere between a medical device and a xenotransplant, the preclinical efficacy and clinical trial data using DPC are included. The review finally provides perspectives on the current standpoint of corneal xenotransplantation in the fields of regenerative medicine.

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“…In Europe, a so‐called centralized approach, that is, communication with EMA, is key prior to conducting late phase multi‐country trials and when a commercial route is considered. It is anticipated that in other countries and regions a similar organization in regulatory oversight is present or need to be developed; for Australia and Asian countries this is the referenced above 5‐8 …”

Section: Conclusion and Perspectivementioning

confidence: 99%

“…It is anticipated that in other countries and regions a similar organization in regulatory oversight is present or need to be developed; for Australia and Asian countries this is the referenced above. [5][6][7][8] Although it is widely accepted that organs, tissues, and cells from porcine origin need extensive testing in animal models before clinical application, the present regulatory oversight brings a new context. Non-clinical in vivo animal transplantation studies are no longer needed to provide data on function, but should focus on collecting data to support a clinical trial application; this extends function measurements with assessment of safety in relevant animal species (eg, infectious pathogen transfer, adverse side effects) and species compatibility.…”

Section: Con Clus I On and Per S Pec Tivementioning

confidence: 99%

“…Reference is made to the situation in the United States (Food and Drug Administration, FDA) and Europe (European Medicines Agency, EMA); specific examples can be limited to either one of these agencies. For the regulatory oversight of xenotransplantation in Japan,5 China, 6 South Korea, 7 and Australia, 8 the reader is referred to publications in a recent issue or in the present issue of Xenotransplantation. References are, where possible, to international organizations like the World Health Organization (WHO) and International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) 9…”

Section: Introductionmentioning

confidence: 99%

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Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects

Schuurman¹,

Hoogendoorn

2020

Xenotransplantation

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During the last years, progress has been made in survival and function of pig‐to‐non‐human primate organ xenotransplantation using organs from genetically modified pigs and immunosuppression regimens that are clinically acceptable. This, together with increased insights into a low risk of pig‐to‐human transmission of porcine endogenous retrovirus, has opened the perspective of starting with first‐in‐human trials with xenogeneic organs. The regulatory path to clinical development is complex. Unlike an organ from human donors, an organ from pigs, either genetically modified or wild‐type pigs, is considered a medicinal product for human use and hence is under regulatory oversight, in the United States by the Food and Drug Administration and in Europe by the national competent authorities of the member states as well as the European Medicines Agency. Related to the status of medicinal product, “(current) good practices” apply in the process of generating a xenogeneic organ through to the transplantation into a patient and life‐long follow‐up. In addition, guidances for xenotransplantation products and genetically modified organisms do apply as well. This commentary focuses on regulatory aspects of transplantation of organs from genetically modified pigs into humans, with the intention to facilitate the interactions between regulatory agencies and institutions (sponsors) in research and clinical development of these organs, to support the perspective of speeding up the process with a proper entry in clinical application, to fill an unmet medical need in patients with end‐stage organ disease.

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Update regarding xenotransplantation in Japan

Cited by 11 publications

References 9 publications

Xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis

Xenotransplantation of neonatal porcine bone marrow‐derived mesenchymal stem cells improves murine hind limb ischemia through lymphangiogenesis and angiogenesis

Corneal xenotransplantation: Where are we standing?

Solid organ xenotransplantation at the interface between research and clinical development: Regulatory aspects

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