A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome

Ronzitti, Giuseppe; Bortolussi, Giulia; Dijk, Remco van; Collaud, Fanny; Charles, Séverine; Leborgne, Christian; Vidal, Pierre; Martin, Samia; Gjata, Bernard; Sola, Marcelo Simon; Wittenberghe, Laetitia van; Vignaud, Alban; Véron, Philippe; Bosma, Piter J.; Muro, Andrés F.; Mingozzi, Federico

doi:10.1038/mtm.2016.49

Cited by 52 publications

(70 citation statements)

References 57 publications

(85 reference statements)

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“…The CNSI mice closely mimic the main features of the human syndrome, with neonatal severe unconjugated hyperbilirubinemia and early neonatal lethality (29,30,38). Although nonintegrative AAV-mediated gene therapy is very effective in rescuing the phenotype in adult CNSI animals (39,40), it requires high doses of liver-specific rAAV8 episomal vectors expressing the UGT1A1 transgene when administered to newborn mutant mice (13,41,42). However, therapeutic efficacy decreases over time and a second administration is necessary to achieve full correction in the long term (41,42).…”

Section: Discussionmentioning

confidence: 90%

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Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

Caneva¹,

Porro²,

Bortolussi³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 90%

“…or i.v. injected as described previously (30,39,40), with the indicated vectors, at the indicated dose, as described in Supplemental Table 5. Briefly, for EGFP editing experiments, WT mice were i.v.…”

Section: Animal Treatmentsmentioning

confidence: 99%

Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

Caneva¹,

Porro²,

Bortolussi³

et al. 2019

JCI Insight

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“…To this aim, we generated AAV8 vectors encoding the selected GAA constructs under the control of a hepatocyte-specific promoter (hAAT) (34), AAV8-hAAT-co GAA , AAV8-hAAT-sp2-Δ8-co GAA , and AAV8-hAAT-sp7-Δ8-co GAA (Fig. 2 and fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although no clinical data are available to date, results in neonatal mice suggest that, after AAV vector–mediated gene transfer, therapeutic efficacy is at least partially lost as the liver grows (34, 62). Future clinical translation efforts will have to address transgene persistence in the liver of pediatric patients (34) and potentially the need for vector read-ministration (22, 63). Nevertheless, the scale-up of our approach to NHPs supports the safety and feasibility of the approach in humans.…”

Section: Discussionmentioning

confidence: 99%

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

et al. 2017

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Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

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“…It is crucial to evaluate the safety, potency, absence of tumorigenicity and toxicity, as well as in vivo biodistribution of the cells in animal models before their clinical development 24 . Cell-free, AAV-mediated gene therapy for CNSI has proved to be very effective in rescuing bilirubin-induced neonatal lethality in Ugt1 −/− mice and Gunn rat [30][31][32] . Cell therapy has been mainly conducted in the Gunn rat 9 .…”

Section: Discussionmentioning

confidence: 99%

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice

Famulari

Navarro-Tableros

Sanchez

et al. 2020

Sci Rep

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Crigler Najjar Syndrome type I (CNSI) is a rare recessive disorder caused by mutations in the Ugt1a1 gene. There is no permanent cure except for liver transplantation, and current therapies present several shortcomings. Since stem cell-based therapy offers a promising alternative for the treatment of this disorder, we evaluated the therapeutic potential of human liver stem cells (HLSC) in immunecompromised NOD SCID Gamma (NSG)/Ugt1 −/− mice, which closely mimic the pathological manifestations in CNSI patients. To assess whether HLSC expressed UGT1A1, decellularised mouse liver scaffolds were repopulated with these cells. After 15 days' culture ex vivo, HLSC differentiated into hepatocyte-like cells showing UGT1A1 expression and activity. For the in vivo human cell engraftment and recovery experiments, DiI-labelled HLSC were injected into the liver of 5 days old NSG/Ugt1 −/− pups which were analysed at postnatal Day 21. HLSC expressed UGT1A1 in vivo, induced a strong decrease in serum unconjugated bilirubin, thus significantly improving phenotype and survival compared to untreated controls. A striking recovery from brain damage was also observed in HLSCinjected mutant mice versus controls. Our proof-of-concept study shows that HLSC express UGT1A1 in vivo and improve the phenotype and survival of NSG/Ugt1 −/− mice, and show promises for the treatment of CNSI.The Crigler Najjar syndrome type I (CNSI; OMIM number 218800) is a rare monogenic disease (0.6 to 1 per 1 000 000 newborns) caused by deficiency in the only enzyme responsible for bilirubin conjugation in the liver, uridine-diphosphate (UDP)-glucuronosyltransferase (UGT) 1A1 1 . The disease is characterised by severe jaundice (elevated blood levels of bilirubin) since birth and a lifelong risk of bilirubin encephalopathy and death by kernicterus if untreated 2,3 . The current treatment for the disease is intensive phototherapy (PT). However, the clinical management is very difficult since CNSI patients need 10-12 hours/day of PT. In addition, patients respond temporarily to PT, as its effectiveness diminishes with age due to skin thickening and decreased surface/body mass ratio, leading to increased risk of unconjugated bilirubin-induced encephalopathy and permanent brain damage 4 . Liver transplantation can improve the prognosis of inherited metabolic diseases, and is currently the only definitive treatment available for CNSI and other severe liver diseases 5 . However, donor organs are scarce.As an alternative to liver transplantation, cell-based therapy has great potential in the treatment of metabolic liver diseases including CNSI, for the possibility of achieving substitution of diseased hepatic cells and restore damage that may not be possible to correct later in life 23 . Importantly, around 5% of replacement of the total liver mass may improve metabolic disorders, and 10% may normalize liver function 24 . For instance, in humans, infusion of 5% of the liver mass efficiently lowered bilirubin levels in CNSI patients 10,25,26 . In our model, by directly d...

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A translationally optimized AAV-UGT1A1 vector drives safe and long-lasting correction of Crigler-Najjar syndrome

Cited by 52 publications

References 57 publications

Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

Coupling AAV-mediated promoterless gene targeting to SaCas9 nuclease to efficiently correct liver metabolic diseases

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

Human liver stem cells express UGT1A1 and improve phenotype of immunocompromised Crigler Najjar syndrome type I mice

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