Columbia Technology Ventures

Mouse model to study prelamin A in aging

This technology is a knock-in mouse model with a mutation in prelamin A that results in progeroid phenotypes but does not reduce lifespan.

Unmet Need: Animal model to study long-term effects of farnesylated prelamin A

Current mouse models to study Hutchinson–Gilford progeria syndrome involve knocking out the gene ZMPSTE24, which encodes the prelamin A processing enzyme. As a result, full length farnesylated prelamin A accumulates and causes progeroid disorders. However, these mice die young and therefore the long-term effects of prelamin A cannot be studied with these models. Farnesylated prelamin A is also implicated in physiological aging, and there are currently no mouse models to study this.

The Technology: Knock-in mouse model of progeroid symptoms with near-normal lifespan

This technology is a mouse model with an amino acid substitution in the prelamin A gene, LMNA, which blocks the ZMPSTE24-catalyzed processing of prelamin A to lamin A. The mice produce only prelamin A, and no mature lamin A protein. They exhibit various progeroid symptoms, similar to the ZMPSTE24 knockout mice. However, they have near-normal lifespans and can therefore be used to study the long-term effects of farnesylated prelamin A. ZMPSTE24 has other functions not related to prelamin A cleavage, which results in the knockout mice having very severe phenotypes and a limited lifespan. This technology can therefore be used to study progeroid disorders independent of the other effects of knocking out ZMPSTE24.

This technology has been validated in mice and in cultured fibroblast cells.

Applications:

  • Long-term study of farnesylated prelamin A
  • Can be used to study various progeroid disorders
  • Model to study prelamin A in physiological aging

Advantages:

  • Near-normal lifespans
  • Phenocopy ZMPSTE24 knockout mice in terms of growth, skull, and other bone defects
  • Exhibit other symptoms like hyperglycemia and decreased body fat content seen in patients
  • Less severe than ZMPSTE24 knockout mice
  • Can study progeroid disorders independent of unrelated ZMPSTE24 knockout effects

Lead Inventor:

Howard Worman, M.D.

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