To provide more effective treatment options for patients with aromatic L-amino acid decarboxylase deficiency (AADCD), a research team led by Dr. Hsiu-Fen Lee, Dr. Chi-Ren Tsai, and Professor Ching-Shiang Chi from the Department of Pediatric Neurology at Taichung Veterans General Hospital has developed an RNA-targeted gene therapy. This therapy addresses abnormal mRNA caused by mutations in the Dopa Decarboxylase (DDC) gene using antisense oligonucleotide (ASO) technology to correct splicing errors and restore normal protein synthesis. By reducing the proportion of mutant mRNA while increasing the levels of normal mRNA, the therapy has shown potential in effectively treating AADCD.

Breakthrough Therapies Needed for Rare Neurological Disorders

AADCD is a rare neurological disorder caused by DDC gene mutations, leading to severe symptoms such as oculogyric crises in infancy and profound motor development impairment, often preventing patients from walking or speaking. While current adeno-associated virus (AAV)-based gene therapy has demonstrated some symptom improvement, it is not a definitive cure, and patients continue to experience persistent oculogyric crises and psychomotor developmental delays.

RNA-Targeted Therapy Corrects Mutant mRNA for Precise Gene Regulation

The core technology behind this RNA-targeted therapy involves ASO molecules that specifically address the c.714+4 A>T mutation in the DDC gene. By regulating the abnormal splicing of DDC mRNA, this approach restores the expression of normal mRNA and promotes the synthesis of functional DDC protein. The ASO molecules achieve this by masking the cryptic splice site on the mutant mRNA, allowing the cell’s splicing machinery to function correctly, ultimately producing functional decarboxylase enzymes.

Experimental data indicate that after ASO treatment, serotonin levels in patient-derived cells significantly increased, along with improved decarboxylase protein levels. Compared to AAV-based gene therapy, RNA-targeted therapy offers two major advantages:

Precision and Reversibility: This approach directly repairs specific RNA molecules, providing a reversible effect and reducing the risk of permanent genomic alterations.

Rapid and Flexible Production: The design and manufacturing process of RNA-targeted therapy is more adaptable and faster, making it suitable for personalized treatment.

Advancing Clinical Trials to Benefit More Patients with Rare Diseases

Dr. Hsiu-Fen Lee emphasized that AADCD is a rare disease with limited treatment options, and RNA-targeted therapy holds promise for significantly improving patients’ symptoms and quality of life. As preclinical studies near completion, the research team aims to commercialize this technology within the next five years and expand its application to other rare genetic disorders. By collaborating with biotechnology companies, they seek to accelerate clinical trials and commercialization efforts, ultimately providing more effective treatment options for patients worldwide.

Resource: 標靶基因療法修復特定RNA改善 AADCD罕病兒運動發展障礙