High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease

Murillo, Oihana; Collantes, María; Gázquez, Cristina; Moreno, Daniel Antunes; Hernández-Alcoceba, Rubén; Barberia, Miren; Ecay, Margarita; Tamarit, Blanche; Douar, Anne; Ferrer, Veronica; Combal, Jean Philippe; Peñuelas, Iván; Bénichou, Bernard; González‐Aseguinolaza, Gloria

doi:10.1016/j.omtm.2022.06.001

Cited by 10 publications

(8 citation statements)

References 28 publications

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“…Notably, our suggestion that MBD −2 and, in particular, MBD −1 are more important for the function than the preceding metal binding domains resonate with two ongoing clinical studies and previous preclinical trials with ambitions to cure Wilsons disease in which an ATP7B protein lacking MBD −6 to MBD −3 (VTX-801) or MBD −6 to MBD −4 (UX701) but with MBD −2 and MBD −1 retained is re-introduced into the patients 58 , 59 . We expect that such ATP7B forms will have maintained copper transport capacity as also shown in animal experiments, but at the same time may lack fine-tuned regulation, and that consequently long-term surveillance of treated patients may be required 60 . Our findings can also be exploited for the design of plant copper pumps with MBD −1 and perhaps MBD −2 for enrichment of copper in edible plants such as rice or accumulation of the metal for removal from contaminated soils.…”

Section: Resultsmentioning

confidence: 76%

Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Guo,

Orädd,

Bågenholm

et al. 2024

Nat Commun

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Copper transporting P-type (P1B-1-) ATPases are essential for cellular homeostasis. Nonetheless, the E1-E1P-E2P-E2 states mechanism of P1B-1-ATPases remains poorly understood. In particular, the role of the intrinsic metal binding domains (MBDs) is enigmatic. Here, four cryo-EM structures and molecular dynamics simulations of a P1B-1-ATPase are combined to reveal that in many eukaryotes the MBD immediately prior to the ATPase core, MBD−1, serves a structural role, remodeling the ion-uptake region. In contrast, the MBD prior to MBD−1, MBD−2, likely assists in copper delivery to the ATPase core. Invariant Tyr, Asn and Ser residues in the transmembrane domain assist in positioning sulfur-providing copper-binding amino acids, allowing for copper uptake, binding and release. As such, our findings unify previously conflicting data on the transport and regulation of P1B-1-ATPases. The results are critical for a fundamental understanding of cellular copper homeostasis and for comprehension of the molecular bases of P1B-1-disorders and ongoing clinical trials.

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Section: Resultsmentioning

confidence: 76%

Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Guo,

Orädd,

Bågenholm

et al. 2024

Nat Commun

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“…Copper-64 ( 64 Cu) positron emission tomography(PET)/ CT scans can be used to quantify copper uptake in the intestines and liver of both patients with WD and healthy individuals. [12][13][14] We have previously shown that a dose of orally administered 64 Cu can be followed by 64 Cu PET/CT showing quantitative hepatic uptake and subsequent biliary excretion. [12,15] We have also demonstrated how the effect of zinc on intestinal copper uptake could be quantified using PET/CT to measure how the treatment reduced hepatic 64 Cu levels after an oral dose of 64 Cu.…”

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans

Kirk,

Munk,

Swenson

et al. 2023

Hepatology

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Background and Aims: Trientine (TRI) and D-penicillamine (PEN) are used to treat copper overload in Wilson disease. Their main mode of action is thought to be through the facilitation of urinary copper excretion. In a recent study, TRI was noninferior to PEN despite lower 24-hour urinary copper excretion than PEN. We tested whether TRI and/or PEN also inhibit intestinal copper absorption. Approach and Results: Sixteen healthy volunteers were examined with positron emission tomography/CT 1 and 15 hours after an oral Copper-64 (64Cu) dose. They then received 7 days of either PEN or TRI (trientine tetrahydrochloride), after which the 64Cu positron emission tomography/CT scans were repeated. Venous blood samples were also collected. Pretreatment to posttreatment changes of the hepatic 64Cu uptake reflect the effect of drugs on intestinal absorption. 64Cu activity was normalized to dose and body weight and expressed as the mean standard uptake value. TRI (n=8) reduced hepatic 64Cu activity 1 hour after 64Cu dose from 6.17 (4.73) to 1.47 (2.97) standard uptake value, p<0.02, and after 15 hours from 14.24 (3.09) to 6.19 (3.43), p<0.02, indicating strong inhibition of intestinal 64Cu absorption. PEN (n=8) slightly reduced hepatic standard uptake value at 15 hours, from 16.30 (5.63) to 12.17 (1.44), p<0.04. Conclusions: In this mechanistic study, we show that TRI inhibits intestinal copper absorption, in addition to its cupriuretic effect. In contrast, PEN has modest effects on the intestinal absorption. This may explain why TRI and PEN are equally effective although urinary copper excretion is lower with TRI. The study questions whether the same therapeutic targets for 24-hour urinary excretion apply to both drugs.

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“…Copper absorption test • Dynamic assessment of copper metabolism and fluxes in the body can be evaluated with radioactive copper tracer, 64Cu. Abnormal copper metabolism with increased hepatic 64Cu retention, reduced fecal excretion of the radiotracer, and altered 64Cu blood kinetics was found in WD patients and in animal models [79,80]. 64Cu incorporation into ceruloplasmin has demonstrated excellent diagnostic accuracy in patients with WD compared to heterozygous control subjects [81].…”

mentioning

confidence: 99%

“…64Cu incorporation into ceruloplasmin has demonstrated excellent diagnostic accuracy in patients with WD compared to heterozygous control subjects [81]. Interestingly, dynamic positron emission tomography (PET) analysis with 64Cu tracer was used in a recent animal study involving gene therapy [80]. This study found that gene therapy restored physiological copper metabolism in WD mice, confirming the mechanism of action, and demonstrated the translational potential of 64Cu-chloride PET to explore gene therapy pharmacodynamics in a minimally invasive and sensitive manner in WD patients.…”

mentioning

confidence: 99%

Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests

Guillaud

Dumortier²,

Couchonnal-Bedoya³

et al. 2023

Diagnostics

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Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies.

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High value of 64Cu as a tool to evaluate the restoration of physiological copper excretion after gene therapy in Wilson’s disease

Cited by 10 publications

References 28 publications

Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Diverse roles of the metal binding domains and transport mechanism of copper transporting P-type ATPases

Effects of trientine and penicillamine on intestinal copper uptake: A mechanistic 64Cu PET/CT study in healthy humans

Wilson Disease and Alpha1-Antitrypsin Deficiency: A Review of Non-Invasive Diagnostic Tests

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