Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients.

Abstract

A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (hUGT1A1) 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-hUGT1A1, 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.

• Authors: Xiaoxia Shi, Sem J Aronson, Lysbeth Ten Bloemendaal, Suzanne Duijst, Robert S Bakker, Dirk R de Waart, Giulia Bortolussi, Fanny Collaud, Ronald P Oude Elferink, Andrés F Muro, Federico Mingozzi, Giuseppe Ronzitti, Piter J Bosma
• Journal: Molecular therapy. Methods & clinical development (Mol Ther Methods Clin Dev) Vol. 20 Pg. 287-297 (Mar 12 2021) ISSN: 2329-0501 [Print] United States
• PMID: 33511243 (Publication Type: Journal Article)
• Copyright: © 2020 The Author(s).