Figure 4.

Summary of the different strategies used to improve delivery of therapeutic agents to the CNS in the treatment of LSDs

(A) Blood-brain barrier (BBB) disruption strategies: (I) ultrasound or (II) hyperosmotic agents can be used to disrupt the integrity of the BBB; (III) stimulation of receptors can increase passage of enzymes and/or stem cells across the BBB. (B) Enzyme replacement therapy can be targeted to the CNS by modifying enzymes directly (I) or using delivery vehicles to facilitate easier passage across the BBB (II). A range of delivery methods (III) including convection-enhanced delivery, direct injection routes, and delivery vehicles can be used to target the CNS. (C) Ex vivo genetic modification of stem cells using gene therapy (I), different pre-conditioning regimes/agents (II), and different injection routes (III) have been trialled to improve CNS targeting in stem and progenitor cell transplantation. (D) Modifications of gene therapy constructs, including optimization of the gene cassette (I) and selection of viral serotype with CNS tropism (II), and specific injection routes (III) can be utilized to target the CNS with in vivo gene therapy approaches