Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain

Matsuzaki, Yasunori; Konno, Ayumu; Mochizuki, Ryuta; Shinohara, Yusuke; Nitta, Keisuke; Okada, Yukihiro; Hirai, Hirokazu

doi:10.1016/j.neulet.2017.11.049

Cited by 142 publications

(112 citation statements)

References 12 publications

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“…A critical question has been how the AAV-PHP.B vectors cross the BBB and whether this mechanism can be translated to other species and, ultimately, humans. The enhanced CNS tropism of AAV-PHP.B and AAV-PHP.eB appears to extend to rats 14,15 , whereas studies testing AAV-PHP.B or related capsids in nonhuman primates (NHPs) have yielded differing outcomes [16][17][18] . Surprisingly, the enhanced CNS tropism of AAV-PHP.B 6,9,[12][13][14][15]19,20 is starkly absent in BALB/cJ mice 16 .…”

Section: Introductionmentioning

confidence: 99%

Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

Huang

Chan

Tobey

et al. 2019

Preprint

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The engineered AAV-PHP.B family of adeno-associated virus efficiently delivers genes throughout the mouse central nervous system. To guide their application across disease models, and to inspire the development of translational gene therapy vectors useful for targeting neurological diseases in humans, we sought to elucidate the host factors responsible for the CNS tropism of AAV-PHP.B vectors. Leveraging CNS tropism differences across mouse strains, we conducted a genome-wide association study, and rapidly identified and verified LY6A as an essential receptor for the AAV-PHP.B vectors in brain endothelial cells. Importantly, this newly discovered mode of AAV binding and transduction is independent of other known AAV receptors and can be imported into different cell types to confer enhanced transduction by the AAV-PHP.B vectors.

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Section: Introductionmentioning

confidence: 99%

Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

Huang

Chan

Tobey

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Viral labeling approaches have shown the most promise; however, clear limitations exist since most enhancer elements are not defined and viral vectors have limited capacity to include large gene elements 40 . Moreover, achieving systemic coverage of the entire brain with viral labeling also remains challenging 57 . We anticipate that the scalability and flexibility of eFLASH will aid organ-wide phenotyping efforts on such model animals.…”

Section: Discussionmentioning

confidence: 99%

Ultrafast immunostaining of organ-scale tissues for scalable proteomic phenotyping

Yun

Park

Cho

et al. 2019

Preprint

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Studying the function and dysfunction of complex biological systems necessitates comprehensive understanding of individual cells. Advancements in three-dimensional (3D) tissue processing and imaging modalities have enabled rapid visualization and phenotyping of cells in their spatial context. However, system-wide interrogation of individual cells within large intact tissue remains challenging, low throughput, and error-prone owing to the lack of robust labeling technologies.Here we introduce a rapid, versatile, and scalable method, eFLASH, that enables complete and uniform labeling of organ-scale tissue within one day. eFLASH dynamically modulates chemical transport and reaction kinetics to establish system-wide uniform labeling conditions throughout the day-long labeling period. This unique approach enables the same protocol to be compatible with a wide range of tissue types and probes, enabling combinatorial molecular phenotyping across different organs and species. We applied eFLASH to generate quantitative maps of various cell types in mouse brains. We also demonstrated multidimensional cell profiling in a marmoset brain block. We envision that eFLASH will spur holistic phenotyping of emerging animal models and disease models to help assess their functions and dysfunctions.

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“…Therefore, it is desirable to screen AAV capsid libraries in cells of human origin rather than in murine or other animal models. This has been clearly evidenced by a highly neurotropic AAV variant (AAV-PHP.B) that had recently been discovered through an in vivo library screen in mice (Deverman et al, 2016) and unfortunately was recently found to exhibit this enhanced tropism in mice only (Hordeaux et al, 2018;Matsuzaki et al, 2018). However, for the purpose of preclinical testing, it is desirable to develop capsids that can transduce murine cells in addition to human cells as this can accelerate the translation of different gene therapy approaches to the clinic.…”

Section: Discussionmentioning

confidence: 99%

Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors

Pekrun

Alencastro

Liu

et al. 2019

Preprint

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While gene transfer using recombinant adeno-associated viral (rAAV) vectors have shown success in some clinical trials, there remain many tissues that are not well transduced. Because of the recent success in reprogramming islet derived cells into functional β-cells in animal models, we constructed two highly complex barcoded replication competent capsid shuffled libraries and selected for high transducing variants on primary human islets. We describe a chimeric capsid (AAV-KP1) that penetrated and transduced primary human islet cells and human embryonic stem cell derived β-cells with up to 10-fold higher efficiency compared to previously studied best in class AAV vectors. Remarkably, this chimeric capsid was also able to transduce both mouse and human hepatocytes at very high levels in a humanized-chimeric mouse model, thus providing a versatile vector which has the potential to be used in both preclinical testing and human clinical trials for both liver-based diseases and diabetes.

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Intravenous administration of the adeno-associated virus-PHP.B capsid fails to upregulate transduction efficiency in the marmoset brain

Cited by 142 publications

References 12 publications

Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

Delivering genes across the blood-brain barrier: LY6A, a novel cellular receptor for AAV-PHP.B capsids

Ultrafast immunostaining of organ-scale tissues for scalable proteomic phenotyping

Using a barcoded AAV capsid library to select for novel clinically relevant gene therapy vectors

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