Extensive Transduction and Enhanced Spread of a Modified AAV2 Capsid in the Non-human Primate CNS

Autor: Kousaku Ohno, John Forsayeth, Amir Mahmoodi, Waldy San Sebastian, Amin Mahmoodi, Krystof S. Bankiewicz, Lamya S. Shihabuddin, Savanah Trewman, Jerusha Naidoo, Catherine R. O'Riordan, Piotr Hadaczek, Lisa M. Stanek, John Bringas, Jennifer Sullivan, Christopher Snieckus, Lluis Samaranch
Rok vydání: 2018
Předmět:
Central Nervous System
0301 basic medicine
Nervous system
Technology
non-human primate
Neurodegenerative
Deep cerebellar nuclei
Medical and Health Sciences
Axonal Transport
Transduction (genetics)
Thalamus
Parvovirinae
Drug Discovery
Motor Neurons
Neurons
nervous system
viral vector
Brain
Gene Therapy
Biological Sciences
Dependovirus
transduction
Infusions
Intraventricular
medicine.anatomical_structure
Spinal Cord
Neurological
Molecular Medicine
Original Article
Biotechnology
Primates
Infusions
capsid modification
Intraventricular
brain
Genetic Vectors
Central nervous system
Biology
AAV vectors
Viral vector
03 medical and health sciences
CNS disorders
Genetics
medicine
Animals
Humans
Molecular Biology
Pharmacology
Animal
Neurosciences
spinal cord
Genetic Therapy
Motor neuron
Spinal cord
Disease Models
Animal
030104 developmental biology
Disease Models
Capsid Proteins
Neuroscience
Heparan Sulfate Proteoglycans
Zdroj: Molecular therapy : the journal of the American Society of Gene Therapy, vol 26, iss 10
ISSN: 1525-0016
DOI: 10.1016/j.ymthe.2018.07.008
Popis: The present study was designed to characterize transduction of non-human primate brain and spinal cord with a modified adeno-associated virus serotype 2, incapable of binding to theheparan sulfate proteoglycan receptor, referred to as AAV2-HBKO. AAV2-HBKO was infused into the thalamus, intracerebroventricularly or via a combination of both intracerebroventricular and thalamic delivery. Thalamic injection of this modified vector encoding GFP resulted in widespread CNS transduction that included neurons in deep cortical layers, deep cerebellar nuclei, several subcortical regions, and motor neuron transduction in the spinal cord indicative of robust bidirectional axonal transport. Intracerebroventricular delivery similarly resulted in widespread cortical transduction, with one striking distinction that oligodendrocytes within superficial layers of the cortex were the primary cell type transduced. Robust motor neuron transduction was also observed in all levels of the spinal cord. The combination of thalamic and intracerebroventricular delivery resulted in transduction of oligodendrocytes in superficial cortical layers and neurons in deeper cortical layers. Several subcortical regions were also transduced. Our data demonstrate that AAV2-HBKO is a powerful vector for the potential treatment of a wide number of neurological disorders, and highlight that delivery route can significantly impact cellular tropism and pattern of CNS transduction.
Databáze: OpenAIRE
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