A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna

Abstract

Global gene delivery to the CNS has therapeutic importance for the treatment of neurological disorders that affect the entire CNS. Due to direct contact with the CNS, cerebrospinal fluid (CSF) is an attractive route for CNS gene delivery. A safe and effective route to achieve global gene distribution in the CNS is needed, and administration of genes through the cisterna magna (CM) via a suboccipital puncture results in broad distribution in the brain and spinal cord. However, translation of this technique to clinical practice is challenging due to the risk of serious and potentially fatal complications in patients. Herein, we report development of a gene therapy delivery method to the CM through adaptation of an intravascular microcatheter, which can be safely navigated intrathecally under fluoroscopic guidance. We examined the safety, reproducibility, and distribution/transduction of this method in sheep using a self-complementary adeno-associated virus 9 (scAAV9)-GFP vector. This technique was used to treat two Tay-Sachs disease patients (30 months old and 7 months old) with AAV gene therapy. No adverse effects were observed during infusion or post-treatment. This delivery technique is a safe and minimally invasive alternative to direct infusion into the CM, achieving broad distribution of AAV gene transfer to the CNS.

Hydrophilic loop 1 of Presenilin-1 and the APP GxxxG transmembrane motif regulate γ-secretase function in generating Alzheimer-causing Aβ peptides

“…The only change introduced would be that in γ-processivity toward APP, not toward other γ-substrates nor other enzymes, which process APP. In light of the development of new viral vectors for CNS delivery ( 34 ), we may proceed to explore the possibilities of gene editing of the GxxxG motif in mice as a targeted “Aβ-shortening” therapy.…”

Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development

“…This modification resulted in reduced toxicity in the DRG, while gene expression was not affected in the rest of the CNS. Recently, Taghian and colleagues developed a novel delivery technique using a microcatheter inserted in the lumbar region that reaches the cisterna magna in the suboccipital space through the spinal canal [ 257 ]. The safety and biodistribution of this delivery approach were first evaluated in sheep.…”

Viral gene therapy for paediatric neurological diseases: progress to clinical reality

“…Detailed natural histories to best define optimal treatment windows, delivery routes, and doses are vital. The encouraging results from SMA, Tay–Sachs disease, and Canavan disease suggest earlier treatment improves efficacy 22,25,31 and highlight the role of newborn screening for these disorders.…”