Chances and Shortcomings of Adenovirus-Mediated ATP7B Gene Transfer in Wilson Disease: Proof of Principle Demonstrated in a Pilot Study with LEC rats

Ha-Hao, D; Merle, Uta; Hofmann, Christian; Wesch, H.; Doll, J.; Auburger, Georg; Tuma, Sabine; Strauß, Michael; Stremmel, Wolfgang

doi:10.1055/s-2002-25151

Cited by 31 publications

(3 citation statements)

References 22 publications

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“…Previous studies demonstrated that introduction of a functional ATP7B gene in LEC rats showed restoration of biliary copper excretion 103. However, these studies did not achieve sustained effects because of the short duration of transgene expression using the first-generation adenoviral vectors.…”

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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“…The limitations of this test are restrictions in copper isotope use in laboratories, so currently it is performed rarely for diagnostic needs. Radioactive copper test is regarded as a useful tool in experimental works where the aim is to restore function of mutated gene and potentially could be used in human gene therapy studies [7,8].…”

Section: To the Editorsmentioning

confidence: 99%

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

Antos

Litwin

Skowrońska

et al. 2020

Neurol Neurochir Pol.

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“…Noninvasive diagnosis of WD, particularly at an early state, will be significant, because copper can be mobilized by drugs or possibly by cell or gene therapy approaches (1,4–7). Previously, diagnosis of WD with radiocopper was unsuccessful.…”

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confidence: 99%

PET with ⁶⁴Cu–Histidine for Noninvasive Diagnosis of Biliary Copper Excretion in Long–Evans Cinnamon Rat Model of Wilson Disease

et al. 2012

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Excretion of copper into bile requires the copper transporter Atp7b, which is deficient in Wilson disease. We hypothesized that a radiocopper–histidine complex would be effective for diagnosing Wilson disease by molecular imaging and tested this hypothesis in the Long–Evans cinnamon (LEC) rat model with Atp7b deficiency. Methods We complexed 64Cu to l-histidine and analyzed clearance from blood, uptake in tissues, and excretion in bile of healthy Long–Evans agouti (LEA) rats versus LEC rats modeling Wilson disease. Sixty-minute dynamic PET recordings were obtained in LEA and LEC rats. Possible effects of acute and chronic liver injury induced by carbon tetrachloride were studied in LEA rats. Atp7b deficiency in LEC rats was reconstituted by transplantation of healthy cells to establish the specificity of findings. Results Examination of blood, tissue, and bile showed that in healthy rats, radiocopper was incorporated in the liver, followed by rapid excretion in bile. Corresponding blood, tissue, and bile studies in LEC rats showed incorporation of radiocopper in the liver but without copper excretion in bile, leading to hepatic retention of the radiotracer. PET showed onset of copper clearance in the liver of LEA rats, whereas liver copper content progressively increased in LEC rats during the 1-h period. Hepatic radiocopper excretion was not altered by either acute or chronic liver injury. In LEC rats with liver repopulation by transplanted healthy hepatocytes, excretion of radiocopper confirmed that Atp7b was responsible for this effect. Conclusion Imaging with the radiocopper–histidine complex successfully identified Atp7b-dependent biliary copper excretion. This principle will advance molecular imaging for Wilson disease.

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Chances and Shortcomings of Adenovirus-Mediated ATP7B Gene Transfer in Wilson Disease: Proof of Principle Demonstrated in a Pilot Study with LEC rats

Abstract: The data demonstrate proof of principle of successful gene therapy in an experimental model of WD. As a consequence of successful but only transient therapeutic effect of adenoviral gene transfer we can now focus more efficient and permanent gene transfer strategies.

Cited by 31 publications

References 22 publications

Update on the clinical management of Wilson's disease

Update on the clinical management of Wilson's disease

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

PET with ⁶⁴Cu–Histidine for Noninvasive Diagnosis of Biliary Copper Excretion in Long–Evans Cinnamon Rat Model of Wilson Disease

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Chances and Shortcomings of Adenovirus-Mediated ATP7B Gene Transfer in Wilson Disease: Proof of Principle Demonstrated in a Pilot Study with LEC rats

Abstract: The data demonstrate proof of principle of successful gene therapy in an experimental model of WD. As a consequence of successful but only transient therapeutic effect of adenoviral gene transfer we can now focus more efficient and permanent gene transfer strategies.

Cited by 31 publications

References 22 publications

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

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

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

PET with 64Cu–Histidine for Noninvasive Diagnosis of Biliary Copper Excretion in Long–Evans Cinnamon Rat Model of Wilson Disease

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Update on the clinical management of Wilson's disease

Update on the clinical management of Wilson's disease

PET with ⁶⁴Cu–Histidine for Noninvasive Diagnosis of Biliary Copper Excretion in Long–Evans Cinnamon Rat Model of Wilson Disease