Next Generation AAV-F Capsid gene therapy rescues disease pathology in a model of Pyruvate Dehydrogenase Complex Deficiency

Keegan, A.; Cetin, O.; Chilcott, E. M.; Antinao Diaz, J. F.; Eaton, S.; Waddington, S. N.; Counsell, J. R.; Rahman, S.; Karda, R.

doi:10.1101/2025.07.30.667478

bioRxiv · 10.1101/2025.07.30.667478

Next Generation AAV-F Capsid gene therapy rescues disease pathology in a model of Pyruvate Dehydrogenase Complex Deficiency

Keegan, A.·Cetin, O.·Chilcott, E. M.·Antinao Diaz, J. F.·Eaton, S.·Waddington, S. N.·Counsell, J. R.·Rahman, S.·Karda, R.

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Abstract

Pyruvate dehydrogenase complex deficiency (PDHD) is a severe mitochondrial disorder most frequently caused by pathogenic variants in PDHA1, leading to neurodevelopmental delay and early mortality, necessitating brain-targeted interventions. Using a brain-specific Pdha1 knockout mouse model, we compared intracerebroventricular delivery of AAV9 capsid and a recently described synthetic neurotropic AAV-F capsid, both expressing human PDHA1 coding sequence driven by a constitutive CAG promoter. Newborn mice received, titre matched AAV9 or AAV-F or AAV9 at ten-fold higher dose. Low-dose AAV-F and high-dose AAV9 significantly improved survival, and restored PDH enzyme activity, metabolite profiles, and brain histopathology to near wild-type levels. However, treated mice showed reduced locomotion by P100 and impaired motor function. Importantly, AAV-F achieved broad CNS transduction with minimal liver expression, outperforming AAV9 at lower dose. There results support the therapeutic potential of AAV-based gene therapy for PDHD and highlighting AAV-F as a promising capsid for efficient, CNS specific delivery.

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Keegan, A., Cetin, O., Chilcott, E. M., Antinao Diaz, J. F., Eaton, S., Waddington, S. N., Counsell, J. R., Rahman, S., Karda, R.. 2025-08-01. Next Generation AAV-F Capsid gene therapy rescues disease pathology in a model of Pyruvate Dehydrogenase Complex Deficiency. https://doi.org/10.1101/2025.07.30.667478

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