Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy

Teresa Brevini; Lisa Swift; Helen Reynolds; John Ong; Richard J. Stopforth; Yogeshkumar Malam; Harry V.M. Spiers; Emilija Jovanovic; Miki Scaravaglio; Vitushan Vakeeswarasarma; James Heslop; Erin Emmett; Brock Andreatta; Emmanouil Athanasiadis; Tessa M. Cacciottolo; Claudia D. Fuchs; Michael Trauner; Sarah A. Hosgood; Teik Choon See; Pavlos Pantelis; Dora Foukaneli; William T.H. Gelson; Paul Gibbs; Kieren Allinson; Gavin J. Pettigrew; Adam Duckworth; Anna L. Paterson; Vassilis G. Gorgoulis; Richard J. Thompson; Arthur Kaser; Vasilis Kosmoliaptsis; Patrick F. Chinnery; Ramon Marti; Jelle van den Ameele; Gwilym J. Webb; Christopher J.E. Watson; Andrew J. Butler; Fotios Sampaziotis

doi:10.1016/j.jhep.2025.07.022

Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy

Teresa Brevini
, Lisa Swift
, Helen Reynolds
, John Ong
, Richard J. Stopforth
, Yogeshkumar Malam
, Harry V.M. Spiers
, Emilija Jovanovic
, Miki Scaravaglio
, Vitushan Vakeeswarasarma
, James Heslop
, Erin Emmett
, Brock Andreatta
, Emmanouil Athanasiadis
, Tessa M. Cacciottolo
, Claudia D. Fuchs
, Michael Trauner
, Sarah A. Hosgood
, Teik Choon See
, Pavlos Pantelis

Dora Foukaneli, William T.H. Gelson, Paul Gibbs, Kieren Allinson, Gavin J. Pettigrew, Adam Duckworth, Anna L. Paterson, Vassilis G. Gorgoulis, Richard J. Thompson, Arthur Kaser, Vasilis Kosmoliaptsis, Patrick F. Chinnery, Ramon Marti, Jelle van den Ameele, Gwilym J. Webb, Christopher J.E. Watson, Andrew J. Butler, Fotios Sampaziotis (Lead / Corresponding author)

Cancer Research

Research output: Contribution to journal › Article › peer-review

1 Citation (Scopus)

1 Downloads (Pure)

Abstract

Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently, perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy. We report the first successful administration of adeno-associated virus serotype 8 (AAV8) vector treatment in the explanted liver of a 34-year-old patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), using machine perfusion. MNGIE is caused by mutations in the thymidine phosphorylase (TYMP) gene, leading to nucleoside accumulation. The patient’s liver was split into anatomical left and right lobes and perfused using separate machine perfusion devices. Prior to treatment, nucleoside accumulation was observed in the perfusate of both lobes, recapitulating the cardinal feature of MNGIE. An AAV8 vector carrying the human TYMP gene was administered in the left lobe with the right serving as a control. AAV8 gene therapy resulted in successful vector uptake, with complete nucleoside clearance within 6 days of administration. Our results constitute the first demonstration of the efficacy of gene therapy for MNGIE in a human organ and provide proof-of-principle for using machine perfusion as a new strategy for disease modelling and testing novel therapeutics, e.g. gene therapy, in explanted livers.

Original language	English
Pages (from-to)	1218-1225
Number of pages	8
Journal	Journal of Hepatology
Volume	83
Issue number	5
Early online date	5 Aug 2025
DOIs	https://doi.org/10.1016/j.jhep.2025.07.022
Publication status	Published - Nov 2025

Keywords

AAV
AAV8
Adenoassociated virus (AAV)
Experimental hepatology
Gene therapy
Genetic disease
Liver transplantation
Machine perfusion
Normothermic machine perfusion

ASJC Scopus subject areas

Hepatology

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.jhep.2025.07.022Licence: CC BY

Final published version
https://doi.org/10.1016/j.jhep.2025.07.022 ©2025 The Authors. Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). J. Hepatol. 2025, 83, 1218–1225)
Final published version, 5.02 MBLicence: CC BY

Cite this

Brevini, T., Swift, L., Reynolds, H., Ong, J., Stopforth, R. J., Malam, Y., Spiers, H. V. M., Jovanovic, E., Scaravaglio, M., Vakeeswarasarma, V., Heslop, J., Emmett, E., Andreatta, B., Athanasiadis, E., Cacciottolo, T. M., Fuchs, C. D., Trauner, M., Hosgood, S. A., See, T. C., ... Sampaziotis, F. (2025). Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy. Journal of Hepatology, 83(5), 1218-1225. https://doi.org/10.1016/j.jhep.2025.07.022

@article{5230759404264894b90269dfebd259c6,

title = "Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy",

abstract = "Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently, perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy. We report the first successful administration of adeno-associated virus serotype 8 (AAV8) vector treatment in the explanted liver of a 34-year-old patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), using machine perfusion. MNGIE is caused by mutations in the thymidine phosphorylase (TYMP) gene, leading to nucleoside accumulation. The patient{\textquoteright}s liver was split into anatomical left and right lobes and perfused using separate machine perfusion devices. Prior to treatment, nucleoside accumulation was observed in the perfusate of both lobes, recapitulating the cardinal feature of MNGIE. An AAV8 vector carrying the human TYMP gene was administered in the left lobe with the right serving as a control. AAV8 gene therapy resulted in successful vector uptake, with complete nucleoside clearance within 6 days of administration. Our results constitute the first demonstration of the efficacy of gene therapy for MNGIE in a human organ and provide proof-of-principle for using machine perfusion as a new strategy for disease modelling and testing novel therapeutics, e.g. gene therapy, in explanted livers.",

keywords = "AAV, AAV8, Adenoassociated virus (AAV), Experimental hepatology, Gene therapy, Genetic disease, Liver transplantation, Machine perfusion, Normothermic machine perfusion",

author = "Teresa Brevini and Lisa Swift and Helen Reynolds and John Ong and Stopforth, \{Richard J.\} and Yogeshkumar Malam and Spiers, \{Harry V.M.\} and Emilija Jovanovic and Miki Scaravaglio and Vitushan Vakeeswarasarma and James Heslop and Erin Emmett and Brock Andreatta and Emmanouil Athanasiadis and Cacciottolo, \{Tessa M.\} and Fuchs, \{Claudia D.\} and Michael Trauner and Hosgood, \{Sarah A.\} and See, \{Teik Choon\} and Pavlos Pantelis and Dora Foukaneli and Gelson, \{William T.H.\} and Paul Gibbs and Kieren Allinson and Pettigrew, \{Gavin J.\} and Adam Duckworth and Paterson, \{Anna L.\} and Gorgoulis, \{Vassilis G.\} and Thompson, \{Richard J.\} and Arthur Kaser and Vasilis Kosmoliaptsis and Chinnery, \{Patrick F.\} and Ramon Marti and \{van den Ameele\}, Jelle and Webb, \{Gwilym J.\} and Watson, \{Christopher J.E.\} and Butler, \{Andrew J.\} and Fotios Sampaziotis",

note = "Publisher Copyright: {\textcopyright} 2025 The Authors.",

year = "2025",

month = nov,

doi = "10.1016/j.jhep.2025.07.022",

language = "English",

volume = "83",

pages = "1218--1225",

journal = "Journal of Hepatology",

issn = "0168-8278",

publisher = "Elsevier",

number = "5",

}

Brevini, T, Swift, L, Reynolds, H, Ong, J, Stopforth, RJ, Malam, Y, Spiers, HVM, Jovanovic, E, Scaravaglio, M, Vakeeswarasarma, V, Heslop, J, Emmett, E, Andreatta, B, Athanasiadis, E, Cacciottolo, TM, Fuchs, CD, Trauner, M, Hosgood, SA, See, TC, Pantelis, P, Foukaneli, D, Gelson, WTH, Gibbs, P, Allinson, K, Pettigrew, GJ, Duckworth, A, Paterson, AL, Gorgoulis, VG, Thompson, RJ, Kaser, A, Kosmoliaptsis, V, Chinnery, PF, Marti, R, van den Ameele, J, Webb, GJ, Watson, CJE, Butler, AJ & Sampaziotis, F 2025, 'Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy', Journal of Hepatology, vol. 83, no. 5, pp. 1218-1225. https://doi.org/10.1016/j.jhep.2025.07.022

TY - JOUR

T1 - Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy

AU - Brevini, Teresa

AU - Swift, Lisa

AU - Reynolds, Helen

AU - Ong, John

AU - Stopforth, Richard J.

AU - Malam, Yogeshkumar

AU - Spiers, Harry V.M.

AU - Jovanovic, Emilija

AU - Scaravaglio, Miki

AU - Vakeeswarasarma, Vitushan

AU - Heslop, James

AU - Emmett, Erin

AU - Andreatta, Brock

AU - Athanasiadis, Emmanouil

AU - Cacciottolo, Tessa M.

AU - Fuchs, Claudia D.

AU - Trauner, Michael

AU - Hosgood, Sarah A.

AU - See, Teik Choon

AU - Pantelis, Pavlos

AU - Foukaneli, Dora

AU - Gelson, William T.H.

AU - Gibbs, Paul

AU - Allinson, Kieren

AU - Pettigrew, Gavin J.

AU - Duckworth, Adam

AU - Paterson, Anna L.

AU - Gorgoulis, Vassilis G.

AU - Thompson, Richard J.

AU - Kaser, Arthur

AU - Kosmoliaptsis, Vasilis

AU - Chinnery, Patrick F.

AU - Marti, Ramon

AU - van den Ameele, Jelle

AU - Webb, Gwilym J.

AU - Watson, Christopher J.E.

AU - Butler, Andrew J.

AU - Sampaziotis, Fotios

PY - 2025/11

Y1 - 2025/11

N2 - Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently, perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy. We report the first successful administration of adeno-associated virus serotype 8 (AAV8) vector treatment in the explanted liver of a 34-year-old patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), using machine perfusion. MNGIE is caused by mutations in the thymidine phosphorylase (TYMP) gene, leading to nucleoside accumulation. The patient’s liver was split into anatomical left and right lobes and perfused using separate machine perfusion devices. Prior to treatment, nucleoside accumulation was observed in the perfusate of both lobes, recapitulating the cardinal feature of MNGIE. An AAV8 vector carrying the human TYMP gene was administered in the left lobe with the right serving as a control. AAV8 gene therapy resulted in successful vector uptake, with complete nucleoside clearance within 6 days of administration. Our results constitute the first demonstration of the efficacy of gene therapy for MNGIE in a human organ and provide proof-of-principle for using machine perfusion as a new strategy for disease modelling and testing novel therapeutics, e.g. gene therapy, in explanted livers.

AB - Ex situ normothermic machine perfusion (NMP) is rapidly emerging as a novel platform for testing therapeutics in human donor livers. Recently, perfusion of explanted patient livers was achieved, raising the possibility of using these diseased organs to increase the fidelity and resolution of drug testing and development. Here, we provide proof-of-principle for the feasibility of this approach in the context of gene therapy. We report the first successful administration of adeno-associated virus serotype 8 (AAV8) vector treatment in the explanted liver of a 34-year-old patient with mitochondrial neurogastrointestinal encephalomyopathy (MNGIE), using machine perfusion. MNGIE is caused by mutations in the thymidine phosphorylase (TYMP) gene, leading to nucleoside accumulation. The patient’s liver was split into anatomical left and right lobes and perfused using separate machine perfusion devices. Prior to treatment, nucleoside accumulation was observed in the perfusate of both lobes, recapitulating the cardinal feature of MNGIE. An AAV8 vector carrying the human TYMP gene was administered in the left lobe with the right serving as a control. AAV8 gene therapy resulted in successful vector uptake, with complete nucleoside clearance within 6 days of administration. Our results constitute the first demonstration of the efficacy of gene therapy for MNGIE in a human organ and provide proof-of-principle for using machine perfusion as a new strategy for disease modelling and testing novel therapeutics, e.g. gene therapy, in explanted livers.

KW - AAV

KW - AAV8

KW - Adenoassociated virus (AAV)

KW - Experimental hepatology

KW - Gene therapy

KW - Genetic disease

KW - Liver transplantation

KW - Machine perfusion

KW - Normothermic machine perfusion

UR - https://www.scopus.com/pages/publications/105017170979

U2 - 10.1016/j.jhep.2025.07.022

DO - 10.1016/j.jhep.2025.07.022

M3 - Article

C2 - 40774626

AN - SCOPUS:105017170979

SN - 0168-8278

VL - 83

SP - 1218

EP - 1225

JO - Journal of Hepatology

JF - Journal of Hepatology

IS - 5

ER -

Successful AAV8 gene therapy on hepatic ex situ machine perfusion for mitochondrial neurogastrointestinal encephalomyopathy

Abstract

Keywords

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this