Gene therapy for aromatic L‐amino acid decarboxylase deficiency: Requirements for safe application and knowledge‐generating follow‐up

Abstract

The autosomal recessive defect of aromatic L‐amino acid decarboxylase (AADC) leads to a severe neurological disorder with manifestation in infancy due to a pronounced, combined deficiency of dopamine, serotonin and catecholamines. The success of conventional drug treatment is very limited, especially in patients with a severe phenotype. The development of an intracerebral AAV2‐based gene delivery targeting the putamen or substantia nigra started more than 10 years ago. Recently, the putaminally‐delivered construct, Eladocagene exuparvovec has been approved by the European Medicines Agency and by the British Medicines and Healthcare products Regulatory Agency. This now available gene therapy provides for the first time also for AADC deficiency (AADCD) a causal therapy, leading this disorder into a new therapeutic era. By using a standardized Delphi approach members of the International Working Group on Neurotransmitter related Disorders (iNTD) developed structural requirements and recommendations for the preparation, management and follow‐up of AADC deficiency patients who undergo gene therapy. This statement underlines the necessity of a framework for a quality‐assured application of AADCD gene therapy including Eladocagene exuparvovec. Treatment requires prehospital, inpatient and posthospital care by a multidisciplinary team in a specialized and qualified therapy center. Due to lack of data on long‐term outcomes and the comparative efficacy of alternative stereotactic procedures and brain target sites, a structured follow‐up plan and systematic documentation of outcomes in a suitable, industry‐independent registry study are necessary.

Oromandibular Dystonia is a Prominent Feature in Patients with Aromatic L-Amino Acid Decarboxylase (AADC) Deficiency

“…The disease is more prevalent in the Asian population, likely due to a founder effect of a specific mutation [2]. In addition, preliminary results from newborn screening studies in central Europe confirmed the former estimated prevalence of 1-2 in around 500.000 newborns [6].…”

Inherited Pediatric Neurotransmitter Disorders: Case Studies and Long-Term Outcomes

“…Upstaza (eladocagene exuparvovec) was recently approved in the European Union and is the first therapy to treat AADC deficiency. 28 29 With the introduction of gene therapy for AADC deficiency and a potential for alleviating symptoms and modifying the natural progression of the disorder, it becomes even more crucial to recognize and accurately establish an early diagnosis. Consensus guidelines have been brought out in a recently published document that will serve to provide further guidance in managing this challenging condition.…”

Gene therapy for neurotransmitter‐related disorders

“…Over time, it would be of utmost patient benefit to have an international, standardised approach from pre‐screening to post‐gene therapy surveillance, using appropriate disease‐specific registries, to consolidate clinical data, allowing for thorough treatment evaluations, especially in rare diseases like IEM‐NT. 159 …”