In November 2022, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) approved Upstaza (eladocagene exuparvovec) for the treatment of aromatic L-amino acid decarboxylase (AADC) deficiency. The product, which delivers a functional version of AADC using adeno-associated viral (AAV) vectors, has seen been authorized for use across the European Union. The product is delivered via infusion directly to the brain, allowing for more targeted and effective treatment. Prior to Upstaza, there were no therapeutic options available for individuals with AADC deficiency.
Now, in March 2023, the European Pharmaceutical Review reports that the National Institute for Health and Care Excellence (NICE) has released final draft guidance recommending Upstaza for individuals aged 18 months or older with AADC deficiency. NICE Guidance provides evidence-based recommendations using independent committees; these recommendations are also evaluated by various stakeholders. The final guidance is expected to be published in April 2023. Part of the current recommendation hinges on NICE’s understanding that Upstaza showed significant benefits for patients within clinical studies.
If you would like to see the guidance as it stands now, you may do so here.
What is AADC Deficiency?
Aromatic l-amino acid decarboxylase (AADC) deficiency is a very rare genetic disorder caused by DDC gene mutations. Normally, our bodies have an enzyme called L-amino acid decarboxylase. This enzyme catalyzes chemical reactions that produce neurotransmitters: epinephrine, serotonin, norepinephrine, and dopamine. Neurotransmitters help neurons to communicate and play a role in nervous system function. In AADC deficiency, the genetic mutations cause this enzyme to have low activity or otherwise not work properly.
Typically, symptoms begin between the neonatal period and the first few months of life. Symptoms and severity vary from patient to patient, though current estimates share that up to 80% of children with this disorder have severe disease manifestations. Potential symptoms may include:
- Hypotonia (poor/weak muscle tone) in the trunk
- Diarrhea or constipation
- Developmental delays
- Decreased movement (hypokinesia)
- Low blood pressure
- Hypersalivation
- Temperature instability
- Behavioral issues
- Failure to thrive
- Drooping eyelids
- Tremors
- Oculogyric crisis (episodes of uncontrollable agitation, muscle spasms, irritability, and head/neck movements)
- Dystonia
- Nasal congestion
- Involuntary movements of the hands and feet
- Seizures
The above is not an exhaustive list of symptoms associated with this disorder. Although symptoms are not progressive, they may lead to life-threatening complications. Unfortunately, as it stands now, many children with this disorder will not live through childhood. To diagnose AADC deficiency, doctors may use lumbar punctures, genetic testing, as well as test levels of AADC enzyme and 3-O-methyl-dopa (3OMD) in the plasma and blood. Outside of gene therapy like Upstaza, treatment options include monoamine oxidase B inhibitors, pyridoxal phosphate, vitamin B6 supplementation, and dopamine agonists. A multidisciplinary care team is recommended.
