Dataset Information

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.

SUBMITTER: Shi X

PROVIDER: S-EPMC7809245 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Shi Xiaoxia X Aronson Sem J SJ Ten Bloemendaal Lysbeth L Duijst Suzanne S Bakker Robert S RS de Waart Dirk R DR Bortolussi Giulia G Collaud Fanny F Oude Elferink Ronald P RP Muro Andrés F AF Mingozzi Federico F Ronzitti Giuseppe G Bosma Piter J PJ

Molecular therapy. Methods & clinical development 20201203

A clinical trial using adeno-associated virus serotype 8 (AAV8)-human uridine diphosphate glucuronosyltransferase 1A1 (h<i>UGT1A1</i>) 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 a ...[more]

PMID: 33511243

Similar Datasets

Project description:Background and purposeJuvenile xanthogranuloma is a rare clonal, myeloid, neoplastic disorder. Typically, juvenile xanthogranuloma is a self-limited disorder of infancy, often presenting as a solitary red-brown or yellow skin papule/nodule. A small subset of patients present with extracutaneous, systemic juvenile xanthogranuloma, which may include the CNS. The goal of this retrospective study was to evaluate and categorize the neuroimaging findings in a representative cohort of pediatric patients with CNS juvenile xanthogranuloma.Materials and methodsThe brain and/or spine MR imaging data of 14 pediatric patients with pathology-proven juvenile xanthogranuloma were categorized and evaluated for the location; the signal intensity of xanthogranulomas on T1WI, T2WI, DWI, and a matching ADC map for the pattern and degree of contrast enhancement; and the presence of perilesional edema, cysts, or necrosis.ResultsFourteen pediatric patients (8 girls, 6 boys; mean age, 84 months) were included in the study. Patients presented with a wide variety of different symptoms, including headache, seizure, ataxia, strabismus, hearing loss, facial paresis, and diabetes insipidus. Juvenile xanthogranuloma lesions were identified in a number of different sites, including supra- and infratentorial as well as intracranial and spinal leptomeningeal. Five patients were categorized into the neuroradiologic pattern unifocal CNS juvenile xanthogranuloma; 8, into multifocal CNS juvenile xanthogranuloma; and 1, into multifocal CNS juvenile xanthogranuloma with intracranial and spinal leptomeningeal disease. In most cases, xanthogranulomas were small-to-medium intra-axial masses with isointense signal on T1WI (compared with cortical GM), iso- or hyperintense signal on T2WI, had restricted diffusion and perilesional edema. Almost all xanthogranulomas showed avid contrast enhancement. However, we also identified less common patterns with large lesions, nonenhancing lesions, or leptomeningeal disease. Four cases had an additional CT available. On CT, all xanthogranulomas were homogeneously hyperdense (solid component) without evident calcifications.ConclusionsCNS juvenile xanthogranuloma may demonstrate heterogeneous neuroimaging appearances potentially mimicking other diseases, such as primary brain neoplasms, metastatic disease, lymphoma and leukemia, other histiocytic disorders, infections, or granulomatous diseases.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets