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In-vitro Mutagenesis

To learn more about the function of a gene, researchers can observe what happens when the gene is inactivated or “knocked out,” by creating genetically engineered knockout animals. Knockout mice have been particularly useful as models for human diseases such as cancer, Parkinson’s disease, and diabetes.

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Cell-Based Small-Molecule Screening Identifying Proteostasis Regulators Enhancing Factor VIII Missense Mutant

Vishal Srivastava1, Zhigang Liu1, Wei Wei1

  • 1Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, Cleveland, OH 44195, USA.

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Summary

Suberoylanilide hydroxamic acid (SAHA) enhances the secretion and activity of coagulation factor VIII (FVIII) in hemophilia A models. This proteostasis regulator offers a promising therapeutic strategy for FVIII missense mutations.

Keywords:
BiP/GRP78Vorinostatfactor VIIIproteostasis regulatorssecretion

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Area of Science:

  • Biochemistry
  • Genetics
  • Pharmacology

Background:

  • Missense mutations are primary causes of hemophilia A (HA), leading to coagulation factor VIII (FVIII) deficiencies.
  • Current HA treatments are costly and inconvenient, necessitating accessible alternatives.
  • Small molecule drugs present a viable option for improving HA management.

Purpose of the Study:

  • To identify compounds that enhance FVIII secretion and activity.
  • To evaluate suberoylanilide hydroxamic acid (SAHA) as a potential therapeutic agent for HA.
  • To elucidate the mechanism of SAHA's action on FVIII secretion.

Main Methods:

  • Screening drug libraries using cells expressing FVIII-Gaussia luciferase fusion proteins.
  • Assessing SAHA's effect on wild-type and mutant FVIII secretion and activity in vitro.
  • Investigating SAHA's interaction with endoplasmic reticulum chaperones (BiP/GRP78, calreticulin).
  • Evaluating SAHA's efficacy in a mouse model of HA.

Main Results:

  • SAHA significantly improved secretion and activity of wild-type FVIII and common HA missense mutants.
  • SAHA enhanced FVIII interaction with BiP/GRP78, a key chaperone in protein folding.
  • Modulating BiP levels affected SAHA-induced FVIII secretion, confirming BiP's role.
  • In vivo administration of SAHA or a BiP activator increased endogenous FVIII activity in mice.

Conclusions:

  • SAHA acts as a proteostasis regulator, enhancing FVIII secretion and function.
  • SAHA represents a novel therapeutic strategy for HA caused by FVIII missense mutations.
  • Targeting chaperone interactions offers a promising approach for treating genetic disorders involving protein misfolding.