Epidemiology, treatment and burden of Wilson disease in France: A 10-year analysis of the national health insurance database.

BACKGROUND & AIMS: Wilson disease (WD) is a rare hereditary, debilitating disease that is fatal if untreated. Given its low prevalence, collecting longitudinal information on large cohorts of patients is challenging. Analysis of health insurance databases offers an approach to meet this challenge. The aim of this study was to evaluate longitudinal trends in the presentation and management of patients with WD identified in the French national health insurance database (SNDS). METHODS: This retrospective, longitudinal, observational study identified people with WD in the SNDS database through hospitalisation diagnosis codes and long-term illness status between 2009 and 2019 inclusive. For each patient, data were extracted on hospitalisations, liver transplantation, mortality, WD-specific treatments (d-penicillamine, trientine and zinc), disability status and sick leave. RESULTS: 1,928 patients with WD were identified, of whom 1,520 (78.8%) were analysed. Prevalence of WD in 2019 was estimated as 2.2 cases per 100,000. Of the 670 patients first documented between 2010 and 2019, 76.1% were hospitalised at least once for a mean duration of 4.63±10.6 days. 152 patients (10.0%) underwent liver transplantation and 205 died (13.5%). The mean age at death was 57.9 ± 23.1 years. 665 patients (43.8%) received a WD-specific treatment at least once. 167 patients (17.1%) received a government disability pension and 624 (41.1%) benefited from long-term illness status due to WD. CONCLUSIONS: Unexpectedly, less than half of patients with WD received treatment recommended in practice guidelines, which may contribute to a high disease burden in terms of hospitalisations, disability and reduced life expectancy. Improving treatment rates, building patient awareness of long-term disease impact or developing a new paradigm of treatment could make a significant contribution to reducing the disease burden.

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

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.