Wilson's disease at a glance

Wilson's disease (WD) is a rare genetic disorder of impaired copper metabolism that causes severe hepatic and neurologic symptoms. It is lethal without a treatment.

Here are some quick facts:

CAUSE:
Wilson's disease is caused by a deficiency of an intracellular copper transporter called ATP7B. It is necessary for excretion of excess copper stores into the bile. ATP7B impairment results in copper tissue accumulation and subsequent toxicity

INHERITANCE:
Wilson's disease is inherited in an autosomal rececssive manner, which means that typically, each patient has received one copy of the mutated ATP7B gene from each of their parents


PREVALENCE:

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


SYMPTOMS:
disease onset occurs generally between 2nd and 3rd decade of life; patients may present a combination of symtoms and none of these is present in all patients. Because the symptoms are not specific of Wilson's disease, misdiagnosis is possible

  • Hepatic symptoms: elevated ALT and AST enzymes, chronic hepatitis, cirrhosis and, in the most severe cases, acute liver failure that may be associated with hemolytic anemia
  • Neurological symptoms: movement and posture impairment (tremor, choreiform movements, parkinsonism, gait disturbances, rigid dystonia, seizures), speech impairment (dysarthria, pseudobulbar palsy), migraines, headaches or Insomnia
  • Psychiatric symptoms: depression, neuroses, personality changes or psychosis
  • Eye symptoms: Ophthalmic Kayser Fleischer ring (brawn copper deposits at the outer margin of the cornea) are very evocative of Wilson's

DIAGNOSIS:
the diagnosis of Wilson's disease relies on an algorithm that takes into account clinical and laboratory findings

TREATMENT:
all patients diagnosed with Wilson's must be treated to prevent the development of severe complications

  • Oral therapy relies on copper chelators to promote copper excretion and/or zinc salts reduce copper absorption; guidelines and recommendations are available to help and choose the most appropriate treatment for each patient
  • Liver transplant (+ immunosuppressive therapy) is indicated if the oral treatment is unsuccessful or in case of acute liver failure

UNMET MEDICAL NEEDS:

  • With current care, neurologic manifestations improve in only 55 % of the patients, and a few patients deteriorate further which suggests irreversibility; 50% patients have residual neuro symptoms despite treatment
  • Side effects may be serious, especially with chelators that may induce paradoxical neurologic deterioration at treatment onset
  • Lifelong constraining oral therapy for Wilson's disease leads to poor adherence to treatment (up to 50% patients), with the risk of decompensation with acute liver failure and death
  • Liver transplant and associated  immunosuppression carry their own risks

POTENTIAL BENEFITS OF AAV GENE THERAPY, AS A NOVEL APPROACH TO MANAGE WILSON'S DISEASE

  • Alternative to current treatments
  • Restoration a normal physiological copper metabolism
  • Generation of long-lasting effects by a single IV administration
  • Alleviation of the need for repeat oral administration of current treatments and of their associated side effects
  • Optimal adherence to treatments, especially in neurologically/cognitively impaired patients