Full-length ATP7B reconstituted through protein trans-splicing corrects Wilson disease in mice

Padula, Agnese; Petruzzelli, Raffaella; Philbert, Sasha A.; Church, Stephanie J.; Esposito, Federica; Campione, Severo; Monti, M.; Capolongo, Filomena; Perna, Claudia; Nusco, Edoardo; Schmidt, Hartmut; Auricchio, Alberto; Cooper, Garth J. S.; Polishchuk, Roman; Piccolo, Pasquale

doi:10.1016/j.omtm.2022.08.004

Cited by 18 publications

(12 citation statements)

References 40 publications

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“…64,65 A split-approach with two AAV vectors encoding each half of the wild-type transgene with a homologous recombination strategy to obtain the full length ATP7B protein was also successfully tested in Wilson disease mice. 66 These preclinical studies paved the way for liverdirected AAV clinical trials targeting Wilson disease. Two studies are currently recruiting adult Wilson disease patients with stable liver disease: i) the GATEWAY study, sponsored by Vivet Therapeutics, is assessing the safety and efficacy of VTX-801, an AAV-Anc80 capsid encoding the miniATP7B gene, in a phase I/II clinical trial (NCT04537377); ii) the Cyprus 2+ clinical trial, sponsored by Ultragenyx, is assessing safety and efficacy of UX701, an AAV9 vector encoding a miniATP7B gene (NCT04884815).…”

Section: Wilson Diseasementioning

confidence: 99%

Liver‐directed gene therapy for inherited metabolic diseases

Baruteau,

Brunetti‐Pierri,

Gissen

2024

J of Inher Metab Disea

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Gene therapy clinical trials are rapidly expanding for inherited metabolic liver diseases whilst two gene therapy products have now been approved for liver based monogenic disorders. Liver‐directed gene therapy has recently become an option for treatment of haemophilias and is likely to become one of the favoured therapeutic strategies for inherited metabolic liver diseases in the near future. In this review, we present the different gene therapy vectors and strategies for liver‐targeting, including gene editing. We highlight the current development of viral and nonviral gene therapy for a number of inherited metabolic liver diseases including urea cycle defects, organic acidaemias, Crigler–Najjar disease, Wilson disease, glycogen storage disease Type Ia, phenylketonuria and maple syrup urine disease. We describe the main limitations and open questions for further gene therapy development: immunogenicity, inflammatory response, genotoxicity, gene therapy administration in a fibrotic liver. The follow‐up of a constantly growing number of gene therapy treated patients allows better understanding of its benefits and limitations and provides strategies to design safer and more efficacious treatments. Undoubtedly, liver‐targeting gene therapy offers a promising avenue for innovative therapies with an unprecedented potential to address the unmet needs of patients suffering from inherited metabolic diseases.

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Section: Wilson Diseasementioning

confidence: 99%

Liver‐directed gene therapy for inherited metabolic diseases

Baruteau,

Brunetti‐Pierri,

Gissen

2024

J of Inher Metab Disea

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“…This product has been shown in vitro to have ATP7B activity [35,36]. The effectiveness of adeno-associated vector encoding human ATP7B cDNA variants in a mouse model of WD [34,[36][37][38] in restoring copper metabolism has led to the evaluation of the two gene therapies, UX701 and VTX-801, for the treatment of WD in human studies (NCT04537377; NCT04884815).…”

Section: Gene Therapymentioning

confidence: 99%

Neurological-Type Wilson Disease: Epidemiology, Clinical Manifestations, Diagnosis, and Management

Kipker¹,

Alessi²,

Bojkovic³

et al. 2023

Cureus

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Wilson disease (WD) is a complex metabolic disorder caused by disruptions to copper regulation within the body, leading to an unregulated accumulation of copper within various tissues. A less understood organ affected by the collection of copper is the brain, which further leads to the generation of oxygen-free radicals and resultant demyelination. Healthcare providers must keep the neurological form of WD in their list of differentials when patients present with diverse neurological manifestations. The initial step to diagnosis will be to distinguish the characteristic disease presentation with a thorough history and physical and neurological examination. A high clinical disease suspicion of WD should warrant further investigation by laboratory workup and imaging modalities to support the clinical findings and confirm the diagnosis of WD. Once a WD diagnosis is established, the healthcare provider should treat the underlying biological process of WD symptomatically. This review article discusses the epidemiology and pathogenesis of the neurological form of WD, its clinical and behavioral implications, diagnostic features, and treatment modalities (current and emerging therapies), further aiding healthcare professionals in early diagnosis and management strategies.

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“…In a recent article in Molecular Therapy – Methods and Clinical Development , Padula and co-authors present pre-clinical data for a new approach to gene therapy in Wilson disease (WD). 1 By using dual adeno-associated viral (AAV) vectors combined with split-intein technology to catalyze ligation of two separate peptides, the authors manage to transfect a full-size ATP7B protein to a mouse model of WD. The pre-clinical data from the present study are encouraging and pave the way for future clinical studies.…”

mentioning

confidence: 99%

“…In the case of WD, the ATP7B gene is too large for optimal AAV vector delivery. 1 Therefore, the technologies currently under investigation in clinical trials have addressed this problem by implementing a truncated version of the ATP7B protein with a reduced number of copper-binding domains (two or three) instead of the normal six. While still functional, the protein is less effective in transporting copper, with potential impaired effectiveness of the gene therapy.…”

mentioning

confidence: 99%