Delivery of therapeutic AAV9 vectors via cisterna magna to treat neurological disorders

Intra-cisternal administration of clinical grade adeno-associated virus (AAV) vectors for gene therapy. The AAV manufacturing industry produces a high quality product of well-defined properties. For intra-cisterna magna (ICM) delivery, an established dose of therapeutic virus is injected in the cerebrospinal fluid (CSF)-filled subarachnoid space between the cerebellum and the dorsal side of the medulla oblongata. Overview of available routes for adeno-associated virus 9 (AAV9) delivery to the central nervous system (CNS). Anatomical delivery sites and their respective viral biodistribution profiles along the CNS are highlighted. A summary of pros and cons of each delivery route reveals ICM delivery as the most promising route to target the CNS in its extension. However, Ohno et al. reported that lumbar puncture (LP) can achieve similar results. ICM injection of AAV9 achieves widespread transgene delivery in both brain and spinal cord. This is a distinct benefit over intracerebroventricular (ICV) administration, which targets the brain. ICM delivery leads to reduced dissemination of the vector to peripheral organs (such as the liver), as well as to better evasion of circulating anti-AAV9-neutralising antibodies (Abs), which are recognised bottlenecks of systemic AAV delivery. ICM delivery requires smaller viral doses compared with systemic delivery, improving safety and reducing the costs of clinical-grade vector manufacturing. Moderate dorsal root ganglion (DRG) pathology was reported in studies on non-human primates and piglets, with mononuclear cell infiltrates and secondary axonopathy. ICM is not commonly used in clinical practice due to increased procedural risks, including inadvertent injury to vascular structures and brainstem damage. Lumbar delivery (LP) might achieve similar biodistribution into the brain and spinal cord. Clinical trials based on ICM injection of AAV9 vectors for gene therapy are being conducted in patients with mucopolysaccharidosis type I and IIi,ii, Parkinson’s diseaseiii, frontotemporal dementiaiv, and Gaucher disease type 2v. The AAV9 variant AAVhu68 is being tested in individuals affected by gangliosidosisvi and early infantile Krabbe diseasevii. The figures were generated with Biorender.com No interests are declared. ihttps://clinicaltrials.gov/ct2/show/NCT03580083 iihttps://clinicaltrials.gov/ct2/show/NCT03566043 iiihttps://clinicaltrials.gov/ct2/show/NCT04127578 ivhttps://clinicaltrials.gov/ct2/show/NCT04408625 vhttps://clinicaltrials.gov/ct2/show/NCT04411654 vihttps://clinicaltrials.gov/ct2/show/NCT04713475 viihttps://clinicaltrials.gov/ct2/show/NCT04771416