Wilson's disease at a glance
Wilson disease (WD) is an orphan, inherited, progressive and severely debilitating disorder of copper metabolism which is lethal if left untreated.
Wilson disease is associated with tissue accumulation of copper, as a result of mutations in the ATP7B copper transporter. ATP7B has 2 central roles in copper metabolism:
1. Excretion of excess copper from hepatocytes into the bile ducts
2. Loading of copper ions into ceruloplasmin, and subsequent secretion into the blood circulation
Wilson disease is inherited in an autosomal recessive manner, which means that each patient has received one copy of the mutated ATP7B gene from each parent.
ATP7B transporter deficiency results in tissue accumulation of very toxic “free” (unbound to ceruloplasmin) copper, mainly in the liver and the CNS.
The disease affects approx. one in 30,000 people worldwide
corresponding to a prevalence of approximately 10,000 patients in the US
and 15,000 patients in the EU
Patients affected with Wilson disease remain asymptomatic for years until the first symptoms manifest, typically during the 2nd or 3rd decade of life. They can initially present with hepatic, neurological or psychiatric symptoms, or a combination of all three.
- Hepatic manifestations at presentation are very variable and patients may present with asymptomatic transaminase elevation, chronic hepatitis, cirrhosis or, in the most severe cases, acute liver failure (that may be associated with hemolytic anemia)
- Neurological symptoms may include movement and posture impairment (tremor, choreiform movements, parkinsonism, gait disturbances, rigid dystonia, seizures), speech impairment (dysarthria, pseudobulbar palsy), migraines, headaches and/or insomnia
- Psychiatric manifestations are also very variable and nonspecific and may encompass depression, neuroses, personality changes or psychosis.
An additional symptom, Kayser-Fleischer rings (brown discoloration encircling the iris), is highly evocative of Wilson disease but not always present.
The diagnosis of Wilson disease may be challenging in some cases; it relies on an algorithm (Ferenci score) that takes into account clinical, genetic and biochemical findings.
Because most of the symptoms are not specific, accurate diagnosis is often delayed.
CURRENT TREATMENT OPTIONS:
All patients diagnosed with Wilson's Disease must be treated for life to prevent the development of severe neuropsychiatric and hepatic complications.
Medical intervention - general principle
In general, the treatment follows 2 phases:
- “Decoppering phase” for 6-12 months using copper chelators (mainly D-penicillamine or trientine) to reduce accumulated copper by increasing urinary copper excretion,
- “Maintenance phase” to maintain acceptable copper levels using either reduced doses of copper chelators or zinc salts (zinc reduces intestinal dietary copper absorption). Occasionally, coper chelators and zinc may be used in combination.
Zinc salts may also be used directly in some pre-symptomatic patients.
Current medical treatments are constraining since they must be taken 3-4 times/day for life, at specific times away from meals, and may also be associated with significant side effects.
A low-copper diet is recommended mostly at the time of treatment initiation: foods with very high Cu content (shellfish, nuts, chocolate, mushrooms, and organ meats) should be avoided.
Acute or end stage liver failure generally requires liver transplantation. The literature suggests that depending on the countries and centers, between 5 to 13% of WD patients are liver transplanted. Today, liver transplantation remains the only curative option for Wilson disease, but it is associated with immunosuppression for life and significant morbidity.
UNMET MEDICAL NEEDS:
- up to 50% non-compliance to treatment (Maselbas et al. 2010)
- up to 31% of patients experience severe side effects with widely used D-penicillamine (Merle et al. 2006)
- 10 to 30% of patients get paradoxical neurological worsening upon initiating chelators treatments (Ala et al. 2007)
- only 55% of patients show neurologic improvement (Weiss et al. 2013 - EUROWILSON registry)
- up to 24% of patients with neuro or liver disease progression despite treatment (Merle et al. 2006)
- up to 13% of patients undergo liver transplantation (Beinhardt et al. 2014)
POTENTIAL BENEFITS OF AAV GENE THERAPY, AS A NOVEL APPROACH TO MANAGE WILSON DISEASE
Correction by gene therapy of the defective ATP7B transporter function may ultimately bring a cure to patients with Wilson disease.
The goal of gene therapy is to overcome the main limitations of current management by
- Restoring physiological copper metabolism
- Providing long-lasting benefits with a single intravenous vector administration, alleviating the need for multiple daily administration of current treatments and their associated side effects and therefore optimizing adherence to treatment
- Preventing disease complications (neurological deterioration, psychiatric manifestations and progressive liver diseases) and outweighing significant current therapy costs