4.7 Article

Characterization and Treatment Responsiveness of Genetically Engineered Ornithine Transcarbamylase-Deficient Pig

Journal

JOURNAL OF CLINICAL MEDICINE
Volume 10, Issue 15, Pages -

Publisher

MDPI
DOI: 10.3390/jcm10153226

Keywords

urea cycle disorder; ornithine transcarbamylase; pig; disease model

Funding

  1. Research on Health Sciences Focusing on Drug Innovation, Ministry of Health Labor and Welfare [H26-006]

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To develop novel medical technologies, a genetically engineered ornithine transcarbamylase-deficient (OTCD) pig strain was established and its characteristics and treatment responsiveness were reported. The OTCD pigs were obtained through mating an OTCD carrier female with a wild-type male, with the disease phenotype only appearing in males due to X-linked recessive inheritance. Treatment with nitrogen-scavenging agents based on a clinical protocol significantly extended the survival time of the OTCD pigs.
To develop novel medical technologies, pig disease models are invaluable especially in the final stages of translational research. Recently, we established a genetically engineered ornithine transcarbamylase-deficient (OTCD) pig strain. Here, we report its characterization and treatment responsiveness. OTCD pigs were obtained by mating an OTCD carrier female (OTC-(XXWT)-X-c.186_190del) with a wild-type male. Due to the X-linked recessive mode of inheritance, the disease phenotype emerged only in males. Medication with nitrogen-scavenging agents was based on a clinical protocol. OTCD pigs were born smaller than their wild-type and carrier littermates, showing anemia and faltering. Biochemically, high levels of urinary orotic acid and loss of OTC activity were observed. The natural life course of OTCD pigs was characterized by a decrease in arterial percentage saturation of oxygen and body temperature, as well as an increase in blood ammonia levels; the pigs died in 24.0 +/- 5.0 h (mean +/- SD, n = 6). The established standard medication composed with nitrogen-scavenging agents and transfusion nearly doubled the survival time to 42.4 +/- 13.7 h (n = 6). Our OTCD pig model appropriately mimicked the human pathology. Along with established protocols in handling and medication, this is a first step in developing a large animal disease model that is useful for translational research into novel medical technologies, such as cell transplantation and gene therapy, as well as in relation to urea cycle disorder.

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