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Blocking phospholamban with VHH intrabodies enhances contractility and relaxation in heart failure

Erwin De Genst1,2, Kylie S Foo3,4, Yao Xiao3,4

  • 1Discovery Sciences, R&D, AstraZeneca, Cambridge, UK. erwin.degenst@astrazeneca.com.

Nature Communications
|May 31, 2022
PubMed

Insights

Researchers developed novel intracellular antibodies (intrabodies) to target phospholamban, a protein involved in heart failure. This approach successfully improved cardiac function in a mouse model, offering new therapeutic avenues for heart disease.

Area of Science:

  • Cardiovascular Biology
  • Molecular Medicine
  • Biotechnology

Background:

  • Heart failure is linked to impaired calcium cycling, often caused by the interaction between sarco/endoplasmic reticulum Ca2+ ATPase and phospholamban.
  • Phospholamban is a key therapeutic target, but selective inhibition strategies are lacking.

Purpose of the Study:

  • To develop and apply intracellular antibodies (intrabodies) for modulating phospholamban function in vivo.
  • To investigate the potential of intrabodies as a therapeutic strategy for heart failure.

Main Methods:

  • Utilized a synthetic VHH phage-display library to identify high-affinity intrabodies against phospholamban.
  • Employed modified mRNA transfection for rapid phenotypic screening of intrabodies in primary cells and tissues.
  • Adeno-associated virus (AAV) mediated delivery was used for in vivo application.

Main Results:

  • Identified specific intrabodies targeting different conformational states of phospholamban.
  • Efficiently screened and selected the most effective intrabody using modified mRNA transfection.
  • Demonstrated improvement in cardiac performance in a murine model of heart failure following AAV-mediated intrabody delivery.

Conclusions:

  • Intrabodies represent a viable strategy for targeting intracellular proteins like phospholamban.
  • The combination of intrabody generation, mRNA screening, and AAV delivery offers a promising platform for developing novel heart failure therapies.
  • This approach could uncover unique therapeutic opportunities for cardiac diseases.

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