The Food and Drug Administration says that a new analysis indicating genome editing in cattle can have unintended consequences underscores the importance of its regulatory approach to animal biotechnology. 

“Genome editing is a groundbreaking technology used to introduce intentional genomic alterations in animals and has the potential to improve human and animal health, animal well-being and to enhance food production and quality,” FDA Commissioner Stephen Hahn said in a statement released by the agency Friday. 

“It is paramount, however, that as we move forward, we maintain standards of safety and effectiveness.”

FDA defines all intentionally altered genomic DNA as a new animal drug, irrespective of how or why they were changed. For example, firms that use gene editing to develop pigs with PRRS resistance would have to go through FDA’s process for evaluating a drug. 

The agency’s position has been heavily criticized by the animal ag industry, which says it stifles innovation and is cost-prohibitive.

FDA examined publicly available whole-genome sequencing data from genome-edited cattle. The agency’s analysis, published in Nature Biotechnology, “illustrates … why it is necessary for there to be regulatory oversight of intentional genomic alterations in animals, even when the intended modification seeks to replicate a naturally occurring mutation,” said Steven Solomon, director of FDA’s Center for Veterinary Medicine, in a letter accompanying the analysis.

“The intended genome edit sought to introduce the Celtic POLLED allele into Holstein cattle,” Solomon’s commentary says. “This allele exists in some other cattle breeds and results in the animals lacking horns (or being ‘polled’). As sometimes occurs with germline genomic alterations, however, the editing also produced unintended modifications: a heterozygous insertion of carrier plasmid as well as integration of an extra copy of the repair template.”

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Alison Van Eenennaam, a cooperative extension specialist in animal genomics and biotechnology at the University of California-Davis who has conducted extensive research on gene editing with cattle, told Agri-Pulse in 2018 that "GE animal regulatory burdens are disproportionally high and associated with unaccountable delays and considerable uncertainty."

Contacted Friday, Van Eenennaam said she was "disappointed that the FDA failed to mention that the genome-edited bulls and their offspring were followed for years by researchers at UC Davis and were hornless (polled) and healthy. Additionally, the plasmid was not transmitted to half of the offspring, so in one generation there were animals with just the targeted edit.

"This was all documented in detail in my laboratory’s Nature Biotechnology article published in October of 2019, as discussed in my accompanying Nature Research Bioengineering Community BLOG, “Responsible Science Takes Time.” It is unclear why this paper was not referenced by the FDA," she said. 

Van Eenennaam cited a Nature Biotechnology editorial, "Course Correction,” published along with FDA's paper, which quotes Solomon's commentary: “The existence of an unintended alteration does not necessarily demonstrate that edits of an animal’s genome are unsafe, either to the animal or to anyone consuming food from the animal.”

"In over 30 years, there has yet to be a single compelling case where genetic engineering posed a safety problem in a food animal," the research journal editorial says. "The U.S. Food and Drug Administration is sticking to its plan to carry out mandatory premarket review of all gene-edited livestock, irrespective of trait risk. It should rethink.”

Clint Nesbitt, senior director of science & regulatory affairs for food and agriculture at the Biotechnology Innovation Organization, said BIO understands the need for  premarket safety assessments, but believes the process could be improved upon. BIO is currently reviewing the FDA papers.

Solomon said FDA has started a Veterinary Innovation Program “to provide an ‘all hands on deck’ approach to help developers efficiently navigate the regulatory process, and we are already working with several developers as part of this new program.”

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