A Safe and Reliable Technique for CNS Delivery of AAV Vectors in the Cisterna Magna.
Animals
Catheters
Central Nervous System
/ metabolism
Cisterna Magna
/ metabolism
Dependovirus
/ genetics
Gene Expression
Gene Transfer Techniques
Genes, Reporter
Genetic Therapy
Genetic Vectors
/ administration & dosage
Humans
Injections, Spinal
Magnetic Resonance Imaging
Models, Animal
Sheep
Surgery, Computer-Assisted
Tomography, X-Ray Computed
Transduction, Genetic
Transgenes
Video Recording
AAV clinical trial
AAV gene therapy
AAV9
CSF delivery
Tay-Sachs
cisterna magna
intravascular microcatheter
large animal
lysosomal storage disease
Journal
Molecular therapy : the journal of the American Society of Gene Therapy
ISSN: 1525-0024
Titre abrégé: Mol Ther
Pays: United States
ID NLM: 100890581
Informations de publication
Date de publication:
05 02 2020
05 02 2020
Historique:
received:
10
08
2019
revised:
04
11
2019
accepted:
07
11
2019
pubmed:
10
12
2019
medline:
29
12
2020
entrez:
10
12
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 31813800
pii: S1525-0016(19)30508-8
doi: 10.1016/j.ymthe.2019.11.012
pmc: PMC7002897
pii:
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
411-421Subventions
Organisme : NINDS NIH HHS
ID : F32 NS080488
Pays : United States
Organisme : NINDS NIH HHS
ID : K08 NS096219
Pays : United States
Organisme : NEI NIH HHS
ID : P30 EY003039
Pays : United States
Organisme : NINDS NIH HHS
ID : U01 NS064096
Pays : United States
Informations de copyright
Copyright © 2019. Published by Elsevier Inc.
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