Efficacy of AAV8-h UGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients.
| Autor: | Shi X; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Aronson SJ; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Ten Bloemendaal L; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Duijst S; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Bakker RS; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., de Waart DR; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Bortolussi G; International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy., Collaud F; Genethon, 91000 Evry, France.; Université Paris-Saclay, Université d'Evry, INSERM, Genethon, Integrare Research Unit UMR S951, 91000 Evry, France., Oude Elferink RP; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands., Muro AF; International Centre for Genetic Engineering and Biotechnology, 34149 Trieste, Italy., Mingozzi F; Genethon, 91000 Evry, France., Ronzitti G; Genethon, 91000 Evry, France.; Université Paris-Saclay, Université d'Evry, INSERM, Genethon, Integrare Research Unit UMR S951, 91000 Evry, France., Bosma PJ; Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, AGEM, Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular therapy. Methods & clinical development [Mol Ther Methods Clin Dev] 2020 Dec 03; Vol. 20, pp. 287-297. Date of Electronic Publication: 2020 Dec 03 (Print Publication: 2021). |
| DOI: | 10.1016/j.omtm.2020.11.016 |
| Abstrakt: | A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (h UGT1A1 ) to treat inherited severe unconjugated hyperbilirubinemia (Crigler-Najjar syndrome) is ongoing, but preclinical data suggest that long-term efficacy in children is impaired due to loss of transgene expression upon hepatocyte proliferation in a growing liver. This study aims to determine at what age long-term efficacy can be obtained in the relevant animal model and whether immune modulation allows re-treatment using the same AAV vector. Neonatal, suckling, and juvenile Ugt1a1-deficient rats received a clinically relevant dose of AAV8-h UGT1A1 , and serum bilirubin levels and anti-AAV8 neutralizing antibodies (NAbs) in serum were monitored. The possibility of preventing the immune response toward the vector was investigated using a rapamycin-based regimen with daily intraperitoneal (i.p.) injections starting 2 days before and ending 21 days after vector administration. In rats treated at postnatal day 1 (P1) or P14, the correction was (partially) lost after 12 weeks, whereas the correction was stable in rats injected at P28. Combining initial vector administration with the immune-suppressive regimen prevented induction of NAbs in female rats, allowing at least partially effective re-administration. Induction of NAbs upon re-injection could not be prevented, suggesting that this strategy will be ineffective in patients with low levels of preexisting anti-AAV NAbs. Competing Interests: F.C., G.B., G.R., A.F.M., and F.M. are inventors of patents describing liver gene transfer approaches for metabolic diseases and/or treatment of hyperbilirubinemia. F.M. is an employee of Spark Therapeutics, a Roche company. The remaining authors declare no competing interests. (© 2020 The Author(s).) |
| Databáze: | MEDLINE |
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