Quantitative Systems Pharmacology Model of hUGT1A1‐modRNA Encoding for the UGT1A1 Enzyme to Treat Crigler‐Najjar Syndrome Type 1
Open accessAbstract
Crigler‐Najjar syndrome type 1 (CN1) is an autosomal recessive disease caused by a marked decrease in uridine‐diphosphate‐glucuronosyltransferase (UGT1A1) enzyme activity. Delivery of hUGT1A1‐modRNA (a modified messenger RNA encoding for UGT1A1) as a lipid nanoparticle is anticipated to restore hepatic expression of UGT1A1, allowing normal glucuronidation and clearance of bilirubin in patients. To support translation from preclinical to clinical studies, and first‐in‐human studies, a quantitative systems pharmacology (QSP) model was developed. The QSP model was calibrated to plasma and liver mRNA, and total serum bilirubin in Gunn rats, an animal model of CN1. This QSP model adequately captured the observed plasma and liver biomarker behavior across a range of doses and dose regimens in Gunn rats. First‐in‐human dose projections made using the translated model indicated that 0.5 mg/kg Q4W dose should provide a clinically meaningful and sustained reduction of >5 mg/dL in total bilirubin levels.
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The therapeutic potential of mRNA-based protein replacement therapies has been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I, acute intermittent porphyria, Fabry disease, Crigler-Najjar syndrome type 1, α1 antitrypsin deficiency, methylmalonic acidaemia/aciduria, arginase deficiency, citrin deficiency and glycogen storage disease type I.
“The therapeutic potential of mRNA-based protein replacement therapies has also been tested in other metabolic disorders in preclinical studies, including hereditary tyrosinaemia type I (HTI)142, acute intermittent porphyria222,223, Fabry disease224,225, Crigler–Najjar syndrome type 1 (ref.226), α1 antitrypsin deficiency227, methylmalonic acidaemia/aciduria228, arginase deficiency229, citrin defic”
From Lipid nanoparticles for mRNA delivery (2021) · cites this paper as [226]
Three other GARDs (Crigler-Najjar syndrome type 1, alpha-1 antitrypsin deficiency, and glycogen storage disease type 1) are currently treated by mRNA LNPs in preclinical studies.
“Additionally, there are three other GARDs (Crigler-Najjar syndrome type 1, alpha-1 antitrypsin deficiency, and glycogen storage disease type 1) which are currently treated by mRNA LNPs in preclinical studies (Table 2).[181–183]”
From RNA delivery biomaterials for the treatment of genetic and rare diseases (2019) · cites this paper as [181]
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- Authors
- Apgar, J. F., Tang, J., Singh, P., Balasubramanian, N., Burke, J., Hodges, M. R., Lasaro, M. A., Lin, L., Miliard, B. L., Moore, K., Jun, L. S., Sobolov, S., Wilkins, A. K., & Gao, X.
- Affiliations
- Applied BioMath (United States) (US)
- Alexion Pharmaceuticals, Inc. New Haven Connecticut USA
- Alexion Pharmaceuticals (United States) (US)
- Corresponding author
- Gao, Xiang
- Venue
- CPT: Pharmacometrics & Systems Pharmacology
- Publisher
- Wiley
- Published
- 2018-04-26
- Volume
- 7
- Issue
- 6
- Pages
- 404-412
- ISSN
- 2163-8306 (ISSN-L)
- PMC
- PMC6391595
- OpenAlex
- W2797686837
- Cited by
- 47
- References
- 20
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 3 · 2022: 10 · 2021: 8 · 2020: 2 · 2019: 4 · 2018: 3
- FWCI
- 4.69
- Type
- journal article
- Language
- en
- Update notices
- correction (2020-03-18)
- Open access
- gold
- doi.org
- Licence
- Locations
- CPT Pharmacometrics & Systems Pharmacology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Alexion Pharmaceuticals
- Topics
- Health Sciences › Medicine › Pediatrics, Perinatology and Child Health › Neonatal Health and Biochemistry
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Pharmacogenetics and Drug Metabolism
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Keywords
- Crigler-Najjar syndrome type 1, UGT1A1, hepatic mRNA expression, total bilirubin, first-in-human dosing, glucuronidation, bilirubin clearance
- MeSH terms
- UGT1A1 Enzyme, Animals, Bilirubin, Crigler-Najjar Syndrome, Disease Models, Animal, Humans, Liver, Models, Theoretical, Rats, Gunn, RNA, RNA, Messenger, Glucuronosyltransferase, Genetic Therapy, Treatment Outcome, Rats, Nanoparticles
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