Cre-dependent selection yields AAV variants for widespread gene transfer to the adult brain
Open accessAbstract
Recombinant adeno-associated viruses (rAAVs) are commonly used vehicles for in vivo gene transfer. However, the tropism repertoire of naturally occurring AAVs is limited, prompting a search for novel AAV capsids with desired characteristics. Here we describe a capsid selection method, called Cre recombination-based AAV targeted evolution (CREATE), that enables the development of AAV capsids that more efficiently transduce defined Cre-expressing cell populations in vivo. We use CREATE to generate AAV variants that efficiently and widely transduce the adult mouse central nervous system (CNS) after intravenous injection. One variant, AAV-PHP.B, transfers genes throughout the CNS with an efficiency that is at least 40-fold greater than that of the current standard, AAV9 (refs. 14,15,16,17), and transduces the majority of astrocytes and neurons across multiple CNS regions. In vitro, it transduces human neurons and astrocytes more efficiently than does AAV9, demonstrating the potential of CREATE to produce customized AAV vectors for biomedical applications.
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Viral vectors, such as adeno-associated virus 9 (AAV9), enable widespread gene transfer in the adult brain.
“Viral vectors, such as adeno-associated virus 9 (AAV9), enable widespread gene transfer in the adult brain 234 .”
From Developmental and epileptic encephalopathies (2024) · cites this paper as [234]
The paper reports AAV9-mediated gene transfer in several regions of the adult mouse brain, but identifies the engineered AAV-PHP.B—not AAV9—as the vector that efficiently transduced the entire adult CNS (Abstract, page unavailable). It reports that AAV-PHP.B transferred genes 40–92 times more efficiently than AAV9 in the brain regions examined, so the claim overstates what the paper shows for AAV9. (LLM, conf=0.85)
Experimental — accuracy not yet measuredAAVPHP.B and AAV-PHP.eB offer a more than 40-fold increase in delivery efficiency to the whole CNS.
“For example, AAVPHP.B (146) and AAV-PHP.eB (101) offer a more than 40-fold increase in delivery efficiency to the whole CNS.”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [146]
The paper reports that AAV-PHP.B delivered genes throughout the adult mouse CNS at least 40-fold more efficiently than AAV9; its regional measurements range from 40-fold in the cortex to 92-fold in the striatum. It does not report results for AAV-PHP.eB, and “more than 40-fold” is not accurate for every region measured. (LLM, conf=0.91)
Experimental — accuracy not yet measuredGradinaru's lab developed the CREATE platform and identified PhP.B and PhP.eB, which showed overwhelming superiority of CNS transduction after systemic delivery in some mouse strains but failed to translate into NHPs.
“Based on such strategy, Gradinaru’s lab developed Cre recombination-based AAV targeted evolution (CREATE) platform and successfully identified PhP.B and PhP.eB [64, 65], showing overwhelming superiority of CNS transduction after systemic delivery in some mouse strains but unfortunately failed to translate into NHPs [66, 67].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [64]
The paper’s Abstract describes CREATE and identifies AAV-PHP.B, reporting at least 40-fold greater CNS gene transfer than AAV9 after intravenous injection in adult mice. It does not identify AAV-PHP.eB; the citing sentence pairs this paper with another citation for the variants. The NHP translation claim is attached to separate citations [66, 67], not to this source. (LLM, conf=0.87)
Experimental — accuracy not yet measuredAAV-PHP.B and AAV-PHP.eB show significantly higher efficiency in transporting across the BBB in C57BL/6J mice after intravenous delivery but are starkly absent in BALB/cJ mice and marmosets.
“Gradinaru lab identified AAV-PHP⋅B and AAV-PHP.eB with significant higher efficiencies in transporting across the BBB in C57BL/6 J mice after intravenous delivery but starkly absent in BALB/cJ mice and marmosets [64–67].”
From Designing and optimizing AAV-mediated gene therapy for neurodegenerative diseases: from bench to bedside (2024) · cites this paper as [64]
The gene-transfer results (page unavailable) report significantly greater CNS gene transfer by intravenously delivered AAV-PHP.B than by AAV9, and the Vector biodistribution Methods specify C57Bl/6 mice. Our copy does not report AAV-PHP.eB or test whether either variant lacks this effect in BALB/cJ mice or marmosets. It also discusses BBB transport as a possible intermediate step rather than directly measuring greater BBB crossing. (LLM, conf=0.89)
Experimental — accuracy not yet measuredAAV-PHP.A exhibits selective astrocyte tropism.
“AAV-PHP.A exhibits selective astrocyte tropism (146)”
From Blood-Brain Barrier: From Physiology to Disease and Back (2019) · cites this paper as [146]
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- Authors
- Deverman, B. E., Pravdo, P. L., Simpson, B. P., Kumar, S. R., Chan, K. Y., Banerjee, A., Wu, W.-L., Yang, B., Huber, N., Pasca, S. P., & Gradinaru, V.
- Affiliations
- California Institute of Technology (US)
- Stanford Medicine (US)
- Corresponding author
- Deverman, Benjamin E
- Gradinaru, Viviana
- ORCID
- Venue
- Nature Biotechnology
- Published
- 2016-02
- Volume
- 34
- Issue
- 2
- Pages
- 204-209
- ISSN
- 0733-222X (ISSN-L)
- 1087-0156
- 1546-1696
- PMC
- PMC5088052
- OpenAlex
- W2256579886
- Cited by
- 1,061
- References
- 50
- Citations by year
- 2026: 111 · 2025: 133 · 2024: 112 · 2023: 97 · 2022: 115 · 2021: 121 · 2020: 105 · 2019: 87 · 2018: 88 · 2017: 59 · 2016: 28 · 2013: 1
- FWCI
- 69.84
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Biotechnology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- Funders
- National Institute on Aging (R01AG047664)
- National Institute of Mental Health (R21MH103824, R01MH107800, R01MH100900)
- National Institute of Neurological Disorders and Stroke (DP2NS087949, U01NS090577)
- National Center for Chronic Disease Prevention and Health Promotion (1DP2NS087949)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- CREATE, Cre recombination, AAV9, intravenous injection, astrocytes, neurons
- MeSH terms
- Dependovirus, Animals, Female, Genetic Engineering, Genetic Vectors, Humans, Transfection, Integrases, Mice, HEK293 Cells
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