Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy

Murillo, Oihana; Luqui, Daniel Moreno; Gázquez, Cristina; Martínez-Espartosa, Débora; Navarro-Blasco, Í.; Monreal, J Ignacio; Guembe, Laura; Moreno-Cermeño, Armando; Corrales, Fernando J.; Prieto, Jesús; Hernández-Alcoceba, Rubén; González‐Aseguinolaza, Gloria

doi:10.1016/j.jhep.2015.09.014

Cited by 108 publications

(93 citation statements)

References 26 publications

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“…However, these studies did not achieve sustained effects because of the short duration of transgene expression using the first-generation adenoviral vectors. Recent report using adeno-associated vector serotype 8 (AAV8) encoding the human ATP7B cDNA placed under the control of the liver-specific a1-antitrypsin promoter (AAV8-AAT-ATP7B) showed sustained benefits for 6 months in knockout mouse model of WD and correction of copper overload with normalization of biochemical abnormalities associated with WD 104. Many additional studies are needed, but this may be the dawn of gene therapy in WD.…”

Section: Treatment Of Wdmentioning

confidence: 99%

Update on the clinical management of Wilson's disease

Hedera

2017

TACG

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Wilson’s disease (WD), albeit relatively rare, is an important genetic metabolic disease because of highly effective therapies that can be lifesaving. It is a great imitator and requires a high index of suspicion for correct and timely diagnosis. Neurologic, psychiatric and hepatologic problems in WD are very nonspecific, and we discuss the most common clinical phenotypes. The diagnosis remains laboratory based, and here we review the most important challenges and pitfalls in laboratory evaluation of WD, including the emerging role of genetic testing in WD diagnosis. WD is a monogenic disorder but has very high allelic heterogeneity with >500 disease-causing mutations identified, and new insights into phenotype–genotype correlations are also reviewed. The gold standard of therapy is chelation of excessive copper, but many unmet needs exist because of possible clinical deterioration in treated patients and potential adverse effects associated with currently available chelating medications. We also review the most promising novel therapeutic approaches, including chelators targeting specific cell types, cell transplantation and gene therapy.

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Section: Treatment Of Wdmentioning

confidence: 99%

Update on the clinical management of Wilson's disease

Hedera

2017

TACG

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“…Mice were bred and maintained under pathogen‐free conditions and genotyped at 3 weeks of age as described. Treatments with AAV vectors were performed in male and female mice at 6 or 12 weeks of age by intravenous injection. For urine and feces collection, mice were placed for 24 hours into metabolic cages (Tecniplast s.p.A.; Buguggiate, VA, Italy) and received food and water ad libitum .…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have shown that an adeno‐associated vector (AAV) expressing the ATP7B protein achieves a sustained therapeutic effect in young male WD mice . However, because of the relatively large size of the ATP7B complementary DNA (cDNA), the genome of the vector surpasses its optimal cloning capacity, significantly affecting the production yields of the therapeutic vector.…”

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confidence: 99%

Liver Expression of a MiniATP7B Gene Results in Long‐Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice

et al. 2019

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Gene therapy with an adeno‐associated vector (AAV) serotype 8 encoding the human ATPase copper‐transporting beta polypeptide (ATP7B) complementary DNA (cDNA; AAV8‐ATP7B) is able to provide long‐term copper metabolism correction in 6‐week‐old male Wilson disease (WD) mice. However, the size of the genome (5.2 kilobases [kb]) surpasses the optimal packaging capacity of the vector, which resulted in low‐yield production; in addition, further analyses in WD female mice and in animals with a more advanced disease revealed reduced therapeutic efficacy, as compared to younger males. To improve efficacy of the treatment, an optimized shorter AAV vector was generated, in which four out of six metal‐binding domains (MBDs) were deleted from the ATP7B coding sequence, giving rise to the miniATP7B protein (Δ57‐486‐ATP7B). In contrast to AAV8‐ATP7B, AAV8‐miniATP7B could be produced at high titers and was able to restore copper homeostasis in 6‐ and 12‐week‐old male and female WD mice. In addition, a recently developed synthetic AAV vector, AAVAnc80, carrying the miniATP7B gene was similarly effective at preventing liver damage, restoring copper homeostasis, and improving survival 1 year after treatment. Transduction of approximately 20% of hepatocytes was sufficient to normalize copper homeostasis, suggesting that corrected hepatocytes are acting as a sink to eliminate excess of copper. Importantly, administration of AAVAnc80‐miniATP7B was safe in healthy mice and did not result in copper deficiency. Conclusion: In summary, gene therapy using an optimized therapeutic cassette in different AAV systems provides long‐term correction of copper metabolism regardless of sex or stage of disease in a clinically relevant WD mouse model. These results pave the way for the implementation of gene therapy in WD patients.

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“…More recently, Murillo et al . () achieved human ATP7B cDNA transfer using an adeno‐associated vector serotype 8 under the control of the liver‐specific alpha‐1 antitrypsin promotor. The virus was administered via intravenous injection in 6‐week‐old mice.…”

Section: Rodent Modelsmentioning

confidence: 99%

“…However, the effect on hepatic copper levels was highly variable and the procedure of intracardiac injection was associated with a high mortality of 70% (Roybal et al 2012). More recently, Murillo et al (2016) achieved human ATP7B cDNA transfer using an adenoassociated vector serotype 8 under the control of the liverspecific alpha-1 antitrypsin promotor. The virus was administered via intravenous injection in 6-week-old mice.…”

Section: Treatment Studiesmentioning

confidence: 99%

Animal models of Wilson disease

Reed

Lutsenko²,

Bandmann

2018

Journal of Neurochemistry

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Wilson disease (WD) is an autosomal recessive disorder of copper metabolism manifesting with hepatic, neurological and psychiatric symptoms. The limitations of the currently available therapy for WD (particularly in the management of neuropsychiatric disease), together with our limited understanding of key aspects of this illness (e.g. neurological vs. hepatic presentation) justify the ongoing need to study WD in suitable animal models. Four animal models of WD have been established: the Long-Evans Cinnamon rat, the toxic-milk mouse, the Atp7b knockout mouse and the Labrador retriever. The existing models of WD all show good similarity to human hepatic WD and have been helpful in developing an improved understanding of the human disease. As mammals, the mouse, rat and canine models also benefit from high homology to the human genome. However, important differences exist between these mammalian models and human disease, particularly the absence of a convincing neurological phenotype. This review will first provide an overview of our current knowledge of the orthologous genes encoding ATP7B and the closely related ATP7A protein in C. elegans, Drosophila and zebrafish (Danio rerio) and then summarise key characteristics of rodent and larger mammalian models of ATP7B-deficiency.

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Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy

Cited by 108 publications

References 26 publications

Update on the clinical management of Wilson's disease

Update on the clinical management of Wilson's disease

Liver Expression of a MiniATP7B Gene Results in Long‐Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice

Animal models of Wilson disease

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Long-term metabolic correction of Wilson’s disease in a murine model by gene therapy

Cited by 108 publications

References 26 publications

Update on the clinical management of Wilson&#39;s disease

Update on the clinical management of Wilson&#39;s disease

Liver Expression of a MiniATP7B Gene Results in Long‐Term Restoration of Copper Homeostasis in a Wilson Disease Model in Mice

Animal models of Wilson disease

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Product

Resources

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Update on the clinical management of Wilson's disease

Update on the clinical management of Wilson's disease