Efficacy of AAV8-hUGT1A1 with Rapamycin in neonatal, suckling, and juvenile rats to model treatment in pediatric CNs patients
| Autor: | Piter J. Bosma, Andrés F. Muro, Giulia Bortolussi, Xiaoxia Shi, Sem J. Aronson, Dirk R. de Waart, Ronald P.J. Oude Elferink, Suzanne Duijst, Fanny Collaud, Robert S. Bakker, Lysbeth ten Bloemendaal, Giuseppe Ronzitti, Federico Mingozzi |
|---|---|
| Přispěvatelé: | Graduate School, Tytgat Institute for Liver and Intestinal Research, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Gastroenterology and Hepatology |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Glucuronosyltransferase lcsh:QH426-470 Bilirubin Pharmacology 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Immune system Genetics Medicine Rapamycin lcsh:QH573-671 Molecular Biology Unconjugated hyperbilirubinemia biology business.industry lcsh:Cytology Unconjugated Hyperbilirubinemia AAV Regimen Uridine diphosphate lcsh:Genetics 030104 developmental biology medicine.anatomical_structure chemistry 030220 oncology & carcinogenesis Hepatocyte biology.protein Molecular Medicine Original Article Neutralizing Antibodies Antibody business |
| Zdroj: | Molecular Therapy: Methods & Clinical Development, Vol 20, Iss, Pp 287-297 (2021) Molecular therapy. Methods & clinical development, 20, 287-297. Nature Publishing Group Molecular Therapy. Methods & Clinical Development |
| ISSN: | 2329-0501 |
| Popis: | 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. Graphical Abstract At postnatal day 28, AAV-hUGT1A1 establishes persistent correction of hyperbilirubinemia in Ugt1a1 deficient rats while earlier treatment results in (partial) loss of efficacy overtime. Only in naive animals does immune suppression by rapamycin effectively bloc NAb induction, allowing effective re-treatment. In primed animals, this induction was reduced but not completely prevented. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|