A novel non-invasive route of delivery for lysosomal enzyme to the CNS. Delivery of IDUA to the brain by intranasal administration of laronidase. Delivery of IDUA to the brain by intranasal administration of an AAV vector.
2. Adeno-associated virus (AAV) gene therapy for neurological disease
This review highlights the strategies employed for improving direct and peripheral targeting of therapeutic vectors to CNS tissue, and considers the significance of cellular and tissue transduction specificity, transgene regulation, and other variables that influence achievement of successful therapeutic goals.
Approaches to overcome constraints of CNS discussed, among which include modalities of local administration, strategies to enhance the blood-CNS permeability, intranasal delivery, use of exosomes, and those exploiting targeting of transporters and transcytosis pathways in the endothelial lining.
New developments in AAV vector design are permitting global CNS gene delivery. Expression can be modulated by optimizing both the capsid and genome of vectors. Lysosomal storage diseases represent an immediate target for gene therapy.
The goal of this workshop was to present ways to deliver therapeutics to the brain, including the limitations of each method, and describe ways to track their delivery, safety, and efficacy. Solving the problem of delivery will aid translation of therapeutics for patients suffering from neurodegeneration and other disorders of the brain.
Peripheral-vein infusion of scAAV2/8-LP1-hFIXco resulted in FIX transgene expression at levels sufficient to improve the bleeding phenotype, with few side effects. Although immune-mediated clearance of AAV-transduced hepatocytes remains a concern, this process may be controlled with a short course of glucocorticoids without loss of transgene expression.