A Rationally Engineered Capsid Variant of AAV9 for Systemic CNS-Directed and Peripheral Tissue-Detargeted Gene Delivery in Neonates

Molecular Therapy. Methods & Clinical Development
Dan WangGuangping Gao

Abstract

Adeno-associated virus (AAV) has provided the gene therapy field with the most powerful in vivo gene delivery vector to realize safe, efficacious, and sustainable therapeutic gene expression. Because many clinically relevant properties of AAV-based vectors are governed by the capsid, much research effort has been devoted to the development of AAV capsids for desired features. Here, we combine AAV capsid discovery from nature and rational engineering to report an AAV9 capsid variant, designated as AAV9.HR, which retains AAV9's capability to traverse the blood-brain barrier and transduce neurons. This variant shows reduced transduction in peripheral tissues when delivered through intravascular (IV) injection into neonatal mice. Therefore, when IV AAV delivery is used to treat CNS diseases, AAV9.HR has the advantage of mitigating potential off-target effects in peripheral tissues compared to AAV9. We also demonstrate that AAV9.HR is suitable for peripheral tissue-detargeted CNS-directed gene therapy in a mouse model of a fatal pediatric leukodystrophy. In light of recent success with profiling diversified natural AAV capsid repertoires and the understanding of AAV capsid sequence-structure-function relationship, such a combinatory...Continue Reading

Citations

May 18, 2020·International Journal of Molecular Sciences·Matthew PiechnikShunji Tomatsu
Mar 17, 2020·Journal of Internal Medicine·U ZekonyteC T Moraes
Sep 4, 2020·Journal of Neurochemistry·Thomas J TurnerGabriele Lignani
Feb 7, 2020·International Journal of Molecular Sciences·Walter Acosta, Carole L Cramer
Feb 3, 2019·Nature Reviews. Drug Discovery·Dan WangGuangping Gao
Feb 12, 2020·Nature Reviews. Genetics·Chengwen Li, R Jude Samulski
Mar 17, 2020·Journal of Neural Transmission·John D Elsworth
Nov 18, 2020·Metabolic Brain Disease·Dan LiuYong Diao
Jan 5, 2021·The Journal of Clinical Investigation·Manish MuhuriGuangping Gao
Nov 20, 2020·Molecular Therapy. Methods & Clinical Development·Brahim BelbellaaHélène Puccio
May 21, 2019·Current Opinion in Biomedical Engineering·Esther J LeeJunghae Suh
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Aug 20, 2021·Life Science Alliance·Cristin D DavidsonWilliam J Pavan

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Methods Mentioned

BETA
X-ray
two-hybrid
confocal microscopy
Replacement Therapy
PCR
electrophoresis
Assay
Protein Assay
Fluorescence

Software Mentioned

GraphPad Prism
Voxel PRESS
LCModel
PyMOL
Coot
ImageJ
VIPERdb

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