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©2021 by The International Society for Stem Cell Research. All rights reserved.

No part of this document may be produced in any form without written permission of The International Society for Stem Cell Research.

Appendices

Appendix 1. The Transfer of Human Stem Cells or their Direct Derivatives into Animal Hosts

Recommendation A6.1: Research involving the transfer of human stem cells or their direct neural and/or glial derivatives into the central nervous systems of postnatal animal hosts requires review by institutional animal research oversight committees supplemented by reviewer expertise in stem cell or developmental biology.

  1. For protocols involving the transfer of human stem cells or their direct neural and/or glial derivatives such that they contribute to the central nervous systems of postnatal animal hosts, research review should be conducted by animal research review committees supplemented with expertise in stem cell or developmental biology. Review should be based on a reasonable extension of existing animal research standards, which are themselves based on rational, practical, fact-based assessments of the effects of research manipulations on cognitive and functional outcome measures, as well as on animal health and welfare. 
  2. Additional data collection and monitoring by animal research committees should be commensurate with the anticipated characteristics of the modified animal in the context of the proposed research. Issues regarding the possible change in or enhancement of an animal’s behavior or operationally-assessed cognition should be addressed through diligent application of accepted principles for the humane treatment and protection of animals in research, and primarily through regular animal research oversight mechanisms.
  3. Monitoring and data collection should be based upon a sound assessment of the developmental trajectories of the animal host that may be further affected by taking into account the environmental and epigenetic context in which the donor genes or cells are going to be deployed. It should be grounded in existing knowledge of such trajectories, with reasonable scientific inferences as to their phenotypic and fate potential, with thorough reference to the physiological and behavioral tests and assessments currently available by which to assess the host species.
  4. Research involving the modification of the central nervous system, as established with the introduction of human stem cells or their neural and/or glial derivatives in a way that they contribute to the brains or spinal cords of animal hosts, may attempt to model or directly mimic aspects of human neurological and neuropsychiatric function. As such, this research may demand specialized cognitive and behavioral assessments of the sort conducted in neuroscientific research. There may be an irreducible degree of uncertainty about the internal cognitive processes of any new animal model, in particular how it would manifest distress, anxiety, or other aspects of animal welfare. In such cases, as with transgenic animals, researchers and institutions should familiarize themselves with available options for behavioral response assessment. A baseline of normal behavioral data for the test species and strain should be available before experimentation is permitted, so as to enable clear and rapid identification of behavioral differences or abnormalities associated with treatment and/or human cell transfer. Investigators and institutions should also consider requiring limited pilot studies to produce initial data on the effects of experimental interventions on modified animals, monitoring all deviations from normal behaviors, with prescribed discussion with pertinent animal welfare committees before proceeding to definitive experiments.
  5. Investigators and institutions should also make appropriate adjustments to research protocols to take into account new data or unanticipated responses from animal subjects that may inform or alter the continued permissibility of the animal’s participation in the study. These include identifying any novel signals suggesting a material change in an animal’s condition, comfort, or behavioral state or repertoire, whether by way of deterioration or enhancement. Regular reassessment of animal welfare during the course of experimentation is essential.
  6. Research with a known, intended, or well-grounded significant potential to create some aspect suggestive of human cognition, self-awareness, behavior or behavioral pathology, while not prohibited, should be subject to close scrutiny, taking care to ensure the humane protection of animal subjects. Such studies require a clear and compelling justification, grounded in the potential for significant scientific breakthrough, clinical advance, or both.
  7. Through retained advisors or committee diversity, animal research review committees should ensure that they have sufficient scientific and clinical expertise to make appropriate judgments concerning the matters discussed in these recommendations.

Recommendation A6.2: Researchers using large, complex animal models, such as livestock and non-human primates, should follow international standards for livestock animal and non-human primate research, which call for frequent monitoring of animals whenever there is the potential for unexpected outcomes and unanticipated phenotypes. 

Best practices dictate that research with non-human primates (NHPs) should account for the following (Tardif et al. 2013):

  1. Investigators must justify their choice of an NHP species in light of the goals of the study.
  2. For some NHP species, temporary removal of an individual from its social group may cause it acute stress, and permanent removal may cause distress (the inability to cope with stress). Because of this variability, investigators and veterinarian staff must be aware of normal behaviors of individual NHPs and must know how to identify potential signs of stress and distress.
  3. Because NHPs are valuable experimental subjects, they are often used in serial studies. Both the number of procedures and their consequent levels of burden must be strongly justified by investigators and monitored by trained veterinary staff.
  4. Housing NHPs in social groups best replicates the social interactions they experience in the wild and thereby promotes species-typical behaviors and psychological well-being. For this reason, any singly housed modified NHPs should kept so for the minimum length of time required. The need for single housing should be reviewed by animal research committee members and veterinary staff. Because NHPs are social animals, single housing can produce a reduced range of species-typical behavior, increased environmental stressors, and self-inflicted wounding or withdrawn behavior. Not only could these outcomes affect the welfare of modified NHPs, but they might also confound investigators’ judgements about any potential behavioral changes caused by the transfer per se of human stem cells or their direct derivatives.

Best practices dictate that research with livestock animals should abide by the following standards:

Guide for the Care and Use of Laboratory Animals – guidance document required for PHS funded studies in US and for AAALAC accredited facilities worldwide https://www.aaalac.org/the-guide/

European standards, also a core reference resource for AAALAC  https://www.aaalac.org/pub/?id=E900C0A9-EEB3-1C2E-6A3C-0C84FF348CDD

Research with Agricultural Animals and Wildlife. ILAR Journal, Volume 60, Issue 1, 2019, Pages 66–73.  https://academic.oup.com/ilarjournal/article/60/1/66/5490285

Agricultural Animals as Biomedical Models: Occupational Health and Safety Considerations. ILAR Journal, Volume 59, Issue 2, 2018, Pages 161–167 https://academic.oup.com/ilarjournal/article/59/2/161/5196514#140647793

 

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