Gene Therapy For AADC Deficiency: Advancements And Clinical Implications For Pediatric And Adult Patients
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Abstract
The Aromatic L-amino acid decarboxylase deficiency is a rare autosomal recessive neurometabolic disorder caused by the biallelic mutation to DDC gene, which results in an inadequate synthesis of neurotransmitters, dopamine and serotonin. The disease shows itself in early childhood at the stage of severe delays in development, paralysis of autonomic disorders and motor restrictions. There is a low benefit in symptom control with conventional treatments and no cure of the underlying enzyme defect. Gene therapy, in which beneficial DDC expression has been delivered to the putamen by an adeno-associated virus (Eladocagene exuparvovec, rAAV2-hAADC), has become a disease-modifying therapy. This project first gives a detailed outline of the pathophysiology, clinical manifestation and genetic basis of AADC deficiency, and then thoroughly assesses the present-day approaches to gene therapy. There is evidence in preclinical studies and clinical trial of great and permanent improve in motor and cognitive abilities, notably in early treated children. Eladocagene exuparvovec has had a favorable safety profile where most of the adverse events are of transient nature or procedure-related instead of adverse event-related to the therapy. The project also provides a contrast of the other existing methods of gene therapy, CRISPR-Cas9 and iPSC-based therapies, their limitations in delivery efficiency, immune responses, and ethical issues. It stresses on the necessity of increased access, affordable production and a long-term monitoring. The conclusion suggests the design of the next-generation strategies, such as the extension of targeting serotonergic areas and multimodal combination therapy. Overall, the project views gene therapy as a revolutionary remedy to AADC deficiency, but without overlooking the scientific, clinical, and ethical issues that should be resolved before an extended application of gene therapy to the general population can happen.
