Table 1.

Benefits of a large animal model

	Small animals	Large animals
Examples	rodents, zebrafish, insects, nematodes	NHPs, pigs, dogs, sheep
Sampling	limited blood volumes; difficult to isolate and characterize secondary organs	larger blood volumes and organs for studies of cancer, infectious diseases, and muscular dystrophies
Relevant cellular subsets	incomplete humanization in xenogeneic models (e.g., challenges in generating human myeloid and red blood cells in humanized mice)21	often highly conserved versus human; availability of comparable mutations for modeling (e.g., SCID and DMD dogs)
Relevant anatomical structures	smaller and often not comparable to human (e.g., rodent retina lacks a macula)22	close resemblance to human immune system (NHP), circulatory system (pigs)12, 13, 14
Lifespan	short; limitation for long-term follow-up studies	longer lifespans enable tracking of edited cells for years/decades
Cost	low	high
Ease of manufacturing	labor-intensive process for humanized mice; limited availability of specific human stem cell sources; smaller size enables smaller-scale manufacturing of cell products	larger size facilitates test of manufacturing feasibility at scales closer to human
Route of administration	frequently not relevant to humans (e.g., intraperitoneal or tail vein in rodents)	intravenous and intramuscular dosing, central lines, and other routes highly comparable to humans
Infectious disease models	fewer human pathogens capable of infecting rodents and lower metazoans	broader susceptibility of large animals to human pathogens and closely related strains (e.g., HIV and SIV)23,24
Musculoskeletal disease models	due to shortened lifespan, shorter time frame to study muscle wasting phenotypes, which are often less severe than human phenotypes25	more clinically relevant progressive muscle wasting phenotypes, which can be studied over a longer lifespan

NHP, nonhuman primate; SCID, severe combined immunodeficiency.