Rescue of infant progressive familial intrahepatic cholestasis type 3 mice by repeated dosing of AAV gene therapy.

Autor:	Weber ND; Vivet Therapeutics S.L., Pamplona, Spain., Odriozola L; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, Pamplona, Spain., Ros-Gañán I; Vivet Therapeutics S.L., Pamplona, Spain., García-Porrero G; Department of Pathology, Clínica Universidad de Navarra, Pamplona, Spain., Salas D; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, Pamplona, Spain., Argemi J; Liver Unit, Internal Medicine Department, Clínica Universidad de Navarra and Hepatology Program, CIMA, Universidad de Navarra, Pamplona, Spain.; Division of Medicine, Gastroenterology and Hepatology Department, University of Pittsburgh, Pittsburgh, PA, USA.; Centro de Investigacion Biomedica en Red (CIBER-Ehd), Madrid, Spain., Combal JP; Vivet Therapeutics S.A.S., Paris, France., Kishimoto TK; Selecta Biosciences, Watertown, MA, USA., González-Aseguinolaza G; Vivet Therapeutics S.L., Pamplona, Spain.; Division of Gene Therapy and Regulation of Gene Expression, Cima Universidad de Navarra, Pamplona, Spain.
Jazyk:	angličtina
Zdroj:	JHEP reports : innovation in hepatology [JHEP Rep] 2023 Feb 24; Vol. 5 (5), pp. 100713. Date of Electronic Publication: 2023 Feb 24 (Print Publication: 2023).
DOI:	10.1016/j.jhepr.2023.100713
Abstrakt:	Background & Aims: Gene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration. Here, we tested a strategy of vector re-administration in infant PFIC3 mice with careful evaluation of its oncogenicity - a particular concern surrounding rAAV treatment. Methods: AAV8-MDR3 was re-administered to infant Abcb4 -/- mice 2 weeks after a first dose co-administered with tolerogenic nanoparticles carrying rapamycin (ImmTOR) given at 2 weeks of age. Eight months later, long-term therapeutic efficacy and safety were assessed with special attention paid to the potential oncogenicity of rAAV treatment. Results: Co-administration with ImmTOR mitigated the formation of rAAV-specific neutralising antibodies and enabled an efficacious second administration of AAV8-MDR3, resulting in stable correction of the disease phenotype, including a restoration of bile phospholipid content and healthy liver function, as well as the prevention of liver fibrosis, hepatosplenomegaly, and gallstones. Furthermore, efficacious repeat rAAV administration prevented the appearance of liver malignancies in an animal model highly prone to developing hepatocellular carcinoma. Conclusions: These outcomes provide strong evidence for rAAV redosing through co-administration with ImmTOR, as it resulted in a long-term therapeutic effect in a paediatric liver metabolic disorder, including the prevention of oncogenesis. Impact and Implications: Redosing of gene therapy for inborn hepatobiliary disorders may be essential as effect wanes during hepatocyte division and renewal, particularly in paediatric patients, but the approach may carry long-term risks of liver cancer. Viral vectors carrying a therapeutic gene exerted a durable cure of progressive familial intrahepatic cholestasis type 3 in infant mice and reduced the risk of liver cancer only following a second administration. Competing Interests: NDW, IRG, JPC, and GGA are employees and stockholders of Vivet Therapeutics. TKK is an employee of Selecta Biosciences. All other authors declare no conflict of interest. Please refer to the accompanying ICMJE disclosure forms for further details. (© 2023 The Author(s).)
Databáze:	MEDLINE
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