Gene Therapy on Ruminant Animals

Dear Colleagues,

Genetic diseases in the context of gene therapy have been widely studied, and many of these indications have been successfully recapitulated in mice. However, murine homologues are limited as translational models because of their small size and decreased life span compared to humans, and also because the mutations induced by gene targeting do not always faithfully reflect the clinical manifestations of the corresponding diseases in humans. These limitations could be overcome by employing large animal models.

To date, several large animal models have been successfully utilized in gene therapy and genome editing, such as nonhuman primates, which more closely resemble the clinical manifestations of human diseases. However, there are very few facilities worldwide which are able to manage nonhuman primates, making access to these models difficult or even complicated depending on the legal frame of each country. Therefore, to advance gene therapy, novel preclinical models utilizing ruminants have been established. For example, in March 2016, Raszek et al. published a paper on the use of genomic tools to improve cattle health in the context of infectious diseases (https://www.frontiersin.org/articles/10.3389/fgene.2016.00030/full and https://jbiolres.biomedcentral.com/articles/10.1186/s40709-020-00124-3). This matter raised several issues in the biomedical and veterinary field, crystalized in another paper by de Graeff et al. on the ethics of genome editing in nonhuman animals (https://royalsocietypublishing.org/doi/10.1098/rstb.2018.0106).

Aside from the issues raised, some animals could be of great benefit in studying the efficacy of gene therapy approaches also in the context of monogenic diseases, such as Holstein bulls, because 15% of those carry a point mutation of the bovine CD18 gene (D128G) in a highly conserved region in the extracellular domain, rendering homozygotes of this mutation ideal candidates for studies involving bovine leukocyte adhesion deficiency (BLAD) (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2806185/). Finally, sheep have already been examined in the context of in utero hemopoietic stem cell transplantation (HSCT) (https://pubmed.ncbi.nlm.nih.gov/7902097/), and additionally, they have been excellent in recapitulating corneal transplantation, suggesting that they could potentially contribute to model gene therapy for the eye (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7088656/).

This edition focuses on gene therapy of ruminants and will address issues around the use of genetic manipulation tools on ruminants, the context of this genetic manipulation, i.e. infectious diseases, monogenic diseases, and in utero gene therapy, the ethical concerns raised thereof, and finally the potential that ruminants hold as convincing and efficacious models in recapitulating corresponding human indications in a more faithful way compared to mouse models in terms of physiology, body and organ size, lifespan, and metabolism.

Dr. Eleni Papanikolaou
Guest Editor

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• ruminants
• gene therapy
• genome editing
• ethics in nonhuman animals
• in utero gene therapy
• transgenic animals