TREX1 Mutant Mouse Model

TREX1 is a powerful DNA exonuclease. Point mutations in the TREX1 gene cause a spectrum of lupus-like autoimmune diseases in humans. Knock-in mouse models with orthologous mutations express dysfunctional TREX1 enzyme so preventing DNA degradation and recapitulating systemic lupus and other human autoimmune diseases.

Problem

According to The Lupus Foundation of America, approximately 1.5 million Americans have some form of lupus, a chronic, debilitating autoimmune disorder. There are few therapeutics available, due primarily to a lack of understanding of pathways that cause the disease. While the characteristics of lupus are widely known – patients make antibodies to their own DNA that signal activation of the immune system and disease-response – there is a need for validated animal models of the disease to define mechanisms of DNA sensing and to advance effective autoimmune therapeutics.

Solution

Scientists at Wake Forest School of Medicine have developed and validated a mouse model of lupus based on a genetic mutation present in patients with an inherited form of lupus, familial chilblain lupus. These patients have a heterozygous mutation in the TREX1 gene resulting in a dysfunctional TREX1 D18N enzyme that cannot effectively degrade double-stranded DNA. Impaired degradation of double-stranded DNA triggers cGAS and STING (stimulator of interferon genes) proteins, activating a downstream interferon-mediated immune response and systemic lupus. The TREX1 D18N mice exhibit various characteristics of human lupus, including systemic inflammation, lymphoid hyperplasia, vasculitis and kidney disease.

Competitive Benefits

  • A genetically precise mouse model that exhibits the dysfunctional TREX1àcGASàSTING pathway
  • Mouse model is based on TREX1 D18N genetic mutation known to cause an inherited form of lupus in humans
  • TREX1 D18N mice provide a platform that emulates characteristics of human lupus, including systemic inflammation, lymphoid hyperplasia, vasculitis and kidney disease
  • Male and female mice exhibit similar phenotypes
  • Molecular signature of affected mice evident within three weeks, allowing for early study of disease progression and measurement of therapeutic effect
  • TREX1 D18N homozygous mice breed well with 60% of the population alive after one year

Application Fields

  • Therapeutic development and drug candidate validation for lupus and a wide range of autoimmune diseases
  • A preclinical platform to study lupus and other autoimmune disorders, DNA metabolism and the immune response to cell-free DNA

Publication

Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proceedings of the National Academy of Sciences. Jessica L. Grieves, Jason M. Fye, Scott Harvey, Jason M. Grayson, Thomas Hollis, and Fred W. Perrino.

Stage of Development

A genetically defined validated mouse model of human lupus available for non-exclusive licensing

Inventors

Fred W. Perrino, PhD
Biochemistry

Licensing Contact

Dean Stell
Wake Forest Innovations
dstell@wakehealth.edu
+1.336.716.4896

Reference #: 14-96

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