A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna
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Authors
Taghian, TolooMarosfoi, Miklos G.
Puri, Ajit S.
Cataltepe, Oguz
King, Robert M.
Fernau, Deborah
Batista, Ana Rita
Flotte, Terence R.
McKenna-Yasek, Diane
Tai, Phillip W. L. L
Aronin, Neil
Gounis, Matthew J.
Sena-Esteves, Miguel
Gray-Edwards, Heather L
UMass Chan Affiliations
Department of MedicineDepartment of Microbiology and Physiological Systems
Department of Pediatrics
Department of Neurology
Department of Neurological Surgery
Department of Radiology
Horae Gene Therapy Center
Document Type
Journal ArticlePublication Date
2019-11-16Keywords
AAV clinical trialAAV gene therapy
AAV9
CSF delivery
Tay-Sachs
cisterna magna
intravascular microcatheter
large animal
lysosomal storage disease
Analytical, Diagnostic and Therapeutic Techniques and Equipment
Genetic Phenomena
Genetics and Genomics
Molecular Biology
Nervous System
Radiology
Viruses
Metadata
Show full item recordAbstract
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.Source
Mol Ther. 2019 Nov 16. pii: S1525-0016(19)30508-8. doi: 10.1016/j.ymthe.2019.11.012. [Epub ahead of print] Link to article on publisher's site
DOI
10.1016/j.ymthe.2019.11.012Permanent Link to this Item
http://hdl.handle.net/20.500.14038/48404PubMed ID
31813800Notes
Full author list omitted for brevity. For the full list of authors, see article.
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10.1016/j.ymthe.2019.11.012