# A porcine model of Fanconi anemia

## TL;DR

A pig model of Fanconi anemia shows human-like symptoms, making it a better tool for studying the disease and developing treatments.

## Contribution

The study introduces a porcine model of Fanconi anemia that better replicates human disease features compared to small animal models.

## Key findings

- FANCA disruption in pigs caused skeletal abnormalities and increased chromosomal radials after mitomycin C treatment.
- FANCA null pigs had reduced hematopoietic colony formation and progressive blood cell abnormalities.
- FANCD2 disruption was embryonic lethal in pigs, highlighting its essential role.

## Abstract

Although small animal models of Fanconi anemia (FA) are useful, they do not faithfully replicate many of the clinical features seen in FA patients. We reasoned that a porcine model of FA with its similar physiology and a relatively long lifespan would produce a phenotype more similar to human FA. Targeting FANCA in domestic swine resulted in skeletal abnormalities and extreme sensitivity to interstrand DNA cross-linking agents. In addition, FANCA disruption followed by mitomycin C treatment resulted in a > 10-fold increase in chromosomal radials, a finding that is considered diagnostic for human FA. Bone marrow derived, hematopoietic progenitor cells from a FANCA null pig showed a 75% reduction in colony forming activity compared to wild type. Evaluation of steady state hematopoiesis in the peripheral blood revealed the gradual development of red cell macrocytosis and a reduction in circulating neutrophils. Targeting of FANCD2 failed to produce any biallelic animals demonstrating the loss of FANCD2 function is embryonic lethal in pigs. These results indicate that a porcine model of FANCA holds promise for the development of strategies to prevent the development of bone marrow failure and malignancies in patients with FA.