Efficacy of AAV8-h UGT1A1  with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients

• Published in: Molecular therapy. Methods & clinical development 2021-03, Vol.20, p.287
• Main Authors: Shi, Xiaoxia, Aronson, Sem J, Ten Bloemendaal, Lysbeth, Duijst, Suzanne, Bakker, Robert S, de Waart, Dirk R, Bortolussi, Giulia, Collaud, Fanny, Oude Elferink, Ronald P, Muro, Andrés F, Mingozzi, Federico, Ronzitti, Giuseppe, Bosma, Piter J
• Format: Article
• Language: English
• ISSN: 2329-0501; 2329-0501

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