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Updated: Jul 13, 2026

Isolation of Next-Generation Gene Therapy Vectors through Engineering, Barcoding, and Screening of Adeno-Associated Virus (AAV) Capsid Variants
09:20

Isolation of Next-Generation Gene Therapy Vectors through Engineering, Barcoding, and Screening of Adeno-Associated Virus (AAV) Capsid Variants

Published on: October 18, 2022

Next generation AAV-F capsid gene therapy rescues disease pathology in a model of pyruvate dehydrogenase complex

Anna Keegan1, Özge Çetin1, Ellie M Chilcott1

  • 1EGA-Institute for Women's Health, University College London, London, UK.

Molecular Therapy. Advances
|July 12, 2026
PubMed

Insights

Gene therapy using AAV-F capsids shows promise for treating pyruvate dehydrogenase complex deficiency (PDHD). This approach improved survival and restored brain function in a mouse model, highlighting AAV-F for CNS-specific delivery.

Area of Science:

  • Neuroscience
  • Genetics
  • Biochemistry

Background:

  • Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder.
  • PDHD is often caused by variants in the PDHA1 gene, leading to neurodevelopmental issues and early death.
  • Brain-targeted gene therapy is crucial for treating PDHD.

Purpose of the Study:

  • To compare the efficacy of AAV9 and AAV-F capsids for intracerebroventricular gene delivery of PDHA1.
  • To evaluate the potential of AAV-F as a neurotropic vector for CNS-specific delivery in a PDHD mouse model.

Main Methods:

  • A brain-specific Pdha1 knockout mouse model was used.
  • Intracerebroventricular delivery of AAV9 and AAV-F capsids expressing human PDHA1 was performed in newborn mice.
  • Titer-matched AAV9, AAV-F, and a high-dose AAV9 were administered.

Main Results:

  • Low-dose AAV-F and high-dose AAV9 significantly improved survival and restored PDH enzyme activity, metabolite profiles, and brain histopathology.
  • AAV-F demonstrated broad central nervous system (CNS) transduction with minimal liver expression, outperforming low-dose AAV9.
  • Mice treated later (postnatal day 100) exhibited impaired motor function, suggesting a critical treatment window.

Conclusions:

  • AAV-based gene therapy holds therapeutic potential for PDHD.
  • AAV-F is a promising capsid for efficient and CNS-specific delivery of therapeutic genes for PDHD.
  • Early intervention is critical for optimal outcomes in PDHD gene therapy.

Keywords:
AAV-Fadeno-associated virusclincal translation and pyruvate dehydrogenase deficiencygene supplementationneonatal gene therapypreclinical

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