Genetically engineered pig models for human diseases

Abstract

Although pigs are used widely as models of human disease, their utility as models has been enhanced by genetic engineering. Initially, transgenes were added randomly to the genome, but with the application of homologous recombination, zinc finger nucleases, and transcription activator-like effector nuclease (TALEN) technologies, now most any genetic change that can be envisioned can be completed. To date these genetic modifications have resulted in animals that have the potential to provide new insights into human diseases for which a good animal model did not exist previously. These new animal models should provide the preclinical data for treatments that are developed for diseases such as Alzheimer's disease, cystic fibrosis, retinitis pigmentosa, spinal muscular atrophy, diabetes, and organ failure. These new models will help to uncover aspects and treatments of these diseases that were otherwise unattainable. The focus of this review is to describe genetically engineered pigs that have resulted in models of human diseases.

Keywords: cloning; genetic engineering; swine.

Figure 1

Overview of genetic engineering in the pig. DNA is isolated from growing cells. By using a comparative approach between humans and other species, constructs that are predicted to create a pig with the desired phenotype are designed and built. Once the construct is engineered, it is used to transduce oocytes, to microinject into pronuclei, or to mix with sperm for sperm-mediated gene transfer, or it is introduced into somatic cells by electroporation or transduction. After the desired stable integration into the somatic cells is determined, somatic cell nuclear transfer is used to create embryos. Embryos with genetically engineered genomes are transferred to a surrogate mother, which then carries the pregnancy to term and delivers one to ten piglets with the desired genetic modification(s).

Figure 2

Human SMN1 generates almost exclusively full-length SMN transcripts. Human SMN2, owing to a C-to-T transition in exon 7, generates predominately exon 7–skipped transcripts (SMNΔ7) and very low amounts of full-length SMN transcripts.

Figure 3

Founder SMN^± piglets at 10 days of age.

Figure 4

Organ systems for which genetically engineered pigs have been created.