[This corrects the article DOI: 10.3389/fimmu.2026.1824802.].

BACKGROUND:Progressive familial intrahepatic cholestasis type 2 (PFIC2) is a rare disease affecting the ABCB11 gene, encoding the bile salt export pump (BSEP). BSEP dysfunction impairs bile acid (BA) secretion, causing hepatic damage and leading to pruritus, cholestasis, hepatomegaly, and often fibrosis and end-stage hepatic disease. Treatments include ileal BA transporter inhibitors, surgical bile diversion, or ultimately, liver transplantation. Our aim was to develop a PFIC2 gene therapy approach based on the restoration of BSEP hepatocyte expression. METHODS AND RESULTS:We designed several expression cassettes containing the human ABCB11 gene downstream of either a liver-specific constitutive promoter or a BA-inducible promoter. After in vitro screening, the AAV vectors with the best expression cassette for each promoter were tested in a PFIC2 mouse model. The AAV vector containing the constitutive promoter, named VTX-802, showed higher BSEP expression, resulting in better restoration of BA secretion 3 and 7 weeks post-treatment. We then performed a dose-range-finding study of VTX-802 in 5-week-old female PFIC2 mice in which the therapeutic efficacy was monitored until 5 months of age. Treated mice showed a sustained dose-dependent improvement in serum transaminase levels. These mice also exhibited significant, but partial, correction of hepatomegaly, and increased BA levels in bile and small intestine, indicating partial restoration of normal BA secretion. CONCLUSIONS:VTX-802 restores hepatic BSEP expression and partially corrects disease phenotype in PFIC2 mice. To our knowledge, VTX-802 is the first gene therapy approach that could potentially benefit PFIC2 patients.

IntroductionPre-existing anti-adeno-associated virus (AAV) neutralizing antibodies (NAbs) can impair AAV-mediated gene delivery. VTX-PID (imlifidase) is a streptococcal protease that specifically cleaves immunoglobulin G (IgG) antibodies. NAVIgATE was a first-in-human study of VTX-PID.MethodsThis double-blind controlled study (EUCT number: 2023-503892-83-00) randomized 35 healthy men, stratified by baseline anti-AAV3B NAb levels (intermediate [≤ 1:45] or high [>1:45]) to receive ascending VTX-PID doses (0.075-0.6 mg/kg) or placebo. The primary endpoint was safety. Key secondary endpoints included levels of anti-AAV3B NAbs and total antibodies (TAbs).ResultsVTX-PID resulted in substantial reductions in total IgG, undigested IgG, anti-AAV3B TAb and NAb levels across all doses, followed by gradual full recovery, with effects being sustained longer (2–5 days) at the highest doses. All participants with intermediate NAb levels achieved durable noninhibitory NAb levels (titer ≤1:5), while those with high NAb levels showed reduction but did not reach the noninhibitory level. Most participants experienced VTX-PID-related treatment−emergent adverse events, primarily musculoskeletal complaints of predominately mild to moderate intensity and fully reversible. Transient mild to moderate infusion-associated reactions occurred in four participants, and reversible liver function test elevations in three.DiscussionVTX-PID effectively depleted anti-AAV3B NAbs, with a dose-dependent effect in magnitude and duration. The safety profile was manageable, with few temporary inflammatory events and self-resolving liver enzyme elevations. VTX-PID 0.3 mg/kg was identified as the appropriate dose based on its safety and efficacy profile. In the population with intermediate NAb levels, the 2- to 5-day depletion in anti-AAV3B NAbs supports VTX−PID as a promising pretreatment approach to open a window of opportunity of up to 5 days, broadening eligibility for systemic AAV-based gene therapies.

We developed a comprehensive, mechanistic model of human copper metabolism to support biomarker qualification for VTX-801, an adeno-associated vector-based gene therapy which is being developed to restore the mutated ATP7B copper transporter gene in Wilson disease (WD). The model integrates physiological copper kinetics with pathophysiological features of WD by distinguishing between ceruloplasmin-bound and non-ceruloplasmin-bound copper (NCC), and by explicitly incorporating ATP7B-dependent processes: biliary excretion and ceruloplasmin loading of copper. Literature-derived time-activity data from healthy subjects, heterozygous carriers, and WD patients, as well as clinical radiocopper data in plasma and feces from a pilot study in non-WD subjects, were used for model development and validation. VTX-801's dose-response was quantified in WD mouse models using ceruloplasmin oxidase activity measurement and 64Cu fecal excretion. This enabled derivation of activity factors (AFs) corresponding to restored ATP7B function, with 15% and 40% selected as minimal and optimal efficacy targets. Simulations linked AFs to clinical biomarkers, demonstrating that the 48/2-h plasma radioactivity ratio can effectively differentiate VTX-801 responders from non-responders, providing a decision criterion to safely withdraw standard treatment in participants of a phase 1/2 trial. To broaden applicability beyond radiotracer studies, we simulated "cold" copper kinetics under steady-state conditions, deriving expected values for plasma copper, NCC, urinary copper excretion, and relative exchangeable copper (REC). These simulations suggest that REC may also serve as a suitable and simpler to implement, non-radioactive biomarker for ATP7B gene therapy. This model provides a robust quantitative framework to assess copper-related biomarkers in WD and their response to treatment in silico. Trial Registration: EudraCT number: 2019-001157-13.

ABSTRACT Wilson Disease (WD) is a rare, potentially debilitating and life‐threatening disorder of copper (Cu) metabolism, considered to be inherited in an autosomal recessive manner, since heterozygotes are healthy. The disease is due to mutations in ATP7B, a hepatic Cu transporting P‐type ATPase responsible for the dual role of regulating Cu homeostasis by eliminating excess Cu into the feces and transferring Cu for biosynthetic incorporation into Cu‐dependent enzymes. We conducted a single center open‐label pilot clinical study in 3 healthy volunteers (HV) and 3 WD heterozygotes (HTZ) who received an intravenous dose of 64 Cu. 64 Cu cumulative fecal and therefore biliary Cu excretion over 72 h showed a mean reduction of 3.8‐fold in WD HTZ compared to HV. Studies have demonstrated that ATP7B can form dimers in vitro and in cells. The abnormal Cu metabolism observed in WD HTZ can represent a reduction in ATP7B function in biliary copper excretion if the mutant: normal dimer has a dominant negative effect on the ATP7B transporter proteins, so that only healthy: healthy dimers may be fully active in vivo. Therefore, when considering gene therapy for WD, production of a high number of mRNA transcripts may be necessary to overcome potential dimerization of ATP7B with mutant protein that might exert a negative effect and limit the efficacy of the therapy. Further studies are needed to validate these hypotheses, and attention should be paid to the particular ATP7B mutations present in individuals with WD being considered for gene therapy or gene repair therapies.

BACKGROUND Wilson disease (WD) is a progressive, potentially fatal degenerative disease affecting the liver and central nervous system. Given its low prevalence, collecting data on large cohorts of patients with WD is challenging. Comprehensive insurance claims databases provide powerful tools to collect retrospective data on large numbers of patients with rare diseases. AIM To describe patients with WD in the United States, their treatment and clinical outcome, using a large insurance claims database. METHODS This retrospective, longitudinal study was performed in the Clarivate Real-World Data Product database. All patients with ≥ 2 claims associated with an International Classification of Diseases 10 (ICD-10) diagnostic code for WD (E83.01) between 2016 and 2021 were included and followed until death or study end. Patients were divided into two groups by whether or not they were documented to have received a specific treatment for WD. Clinical manifestations, hospitalisations, liver transplantation and death were documented. RESULTS Overall, 5376 patients with an ICD-10 diagnostic code for WD were identified. The mean age at inclusion was 41.2 years and 52.0% were men. A specific WD treatment was documented for 885 patients (15.1%), although the number of patients taking zinc salts may be underestimated due to over the counter purchase. At inclusion, the mean age of patients with a documented treatment was 36.6 ± 17.8 years vs 42.2 ± 19.6 years in those without a documented treatment. During follow-up, 273 patients (5.1%) died. Compared with the American general population, the standardised mortality ratio was 2.19. The proportion of patients with a documented WD-specific treatment who died during follow-up was 4.0% and the mean age at death 52.7 years. CONCLUSION Patients treated for WD in the United States had an excess early mortality compared with the American population. These findings indicate that there is a significant unmet need for effective treatment for WD in the United States.

Background & Aims:Gene therapy using recombinant adeno-associated virus (rAAV) vector carrying multidrug resistance protein 3 (MDR3) coding sequence (AAV8-MDR3) represents a potential curative treatment for progressive familial intrahepatic cholestasis type 3 (PFIC3), which presents in early childhood. However, patients with the severest form of PFIC3 should receive treatment early after detection to prevent irreversible hepatic fibrosis leading ultimately to liver transplantation or death. This represents a challenge for rAAV-based gene therapy because therapeutic efficacy is expected to wane as rAAV genomes are lost owing to hepatocyte division, and the formation of AAV-specific neutralising antibodies precludes re-administration. Here, we tested a strategy of vector re-administration in infant PFIC3 mice with careful evaluation of its oncogenicity - a particular concern surrounding rAAV treatment. Methods:AAV8-MDR3 was re-administered to infant Abcb4 -/- mice 2 weeks after a first dose co-administered with tolerogenic nanoparticles carrying rapamycin (ImmTOR) given at 2 weeks of age. Eight months later, long-term therapeutic efficacy and safety were assessed with special attention paid to the potential oncogenicity of rAAV treatment. Results:Co-administration with ImmTOR mitigated the formation of rAAV-specific neutralising antibodies and enabled an efficacious second administration of AAV8-MDR3, resulting in stable correction of the disease phenotype, including a restoration of bile phospholipid content and healthy liver function, as well as the prevention of liver fibrosis, hepatosplenomegaly, and gallstones. Furthermore, efficacious repeat rAAV administration prevented the appearance of liver malignancies in an animal model highly prone to developing hepatocellular carcinoma. Conclusions:These outcomes provide strong evidence for rAAV redosing through co-administration with ImmTOR, as it resulted in a long-term therapeutic effect in a paediatric liver metabolic disorder, including the prevention of oncogenesis. Impact and implications:Redosing of gene therapy for inborn hepatobiliary disorders may be essential as effect wanes during hepatocyte division and renewal, particularly in paediatric patients, but the approach may carry long-term risks of liver cancer. Viral vectors carrying a therapeutic gene exerted a durable cure of progressive familial intrahepatic cholestasis type 3 in infant mice and reduced the risk of liver cancer only following a second administration.

The aim of this study was to evaluate longitudinal trends in the epidemiology and management of patients with WD (Wilson disease) identified in the French national health insurance database (SNDS).