Gene therapy using AAV vectors for pediatric neurological disorders

Abstract

  Gene therapy holds promise for many pediatric neurological disorders, particularly those caused by single gene mutations. Adeno-associated virus (AAV) vectors have the potential for long-term expression in non-dividing neurons. AAV9, known for its ability to cross the blood-brain barrier and efficiently transduce neurons, has become a mainstay in AAV gene therapy for neurological diseases. In fact, an intravenous drug with the AAV9 vector carrying the SMN gene for spinal muscular atrophy has become the first insurance-covered treatment for neurological diseases, yielding positive outcomes. We performed a clinical study on gene therapy for aromatic L-amino acid decarboxylase deficiency caused by variants in the DDC gene essential for dopamine synthesis. Our findings showed that vector injection into the striatum improved motor function and resolved dystonia in all cases. Currently, we are conducting physician-led clinical trials. We are preparing for clinical trials for GLUT1 deficiency and Niemann-Pick disease type C. For widespread vector introduction into the brain, the delivery route will involve lumbar puncture and advancing catheters into the cisterna magna for vector injection. Gene therapy using AAV vectors is only suitable for certain diseases, which include disorders with clear single-gene candidates, functional disorders, diseases where gene overexpression poses no issues and functional recovery is expected with gene introduction into specific cells, and diseases with model animals for assessing therapeutic effects. Considering the continued advances in the development of AAV vectors and administration methods, an increase in the number of target diseases for gene therapy can be expected soon.