AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods

Palaschak, Brett; Herzog, Roland W.; Markusic, David M.

doi:10.1007/978-1-4939-9139-6_20

Cited by 24 publications

(19 citation statements)

References 159 publications

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“…4C,D; Colella et al 2018). It is worth noting that as the genomic DNA was extracted from pieces of total livers, the effective activity is likely to be underestimated because hepatocytes make up 70% of the liver's mass (Palaschak et al 2019). Under the same experimental conditions, the levels of in vivo editing achieved with AAV-St1Cas9 v3 were comparable to the ones obtained using the gold standard AAV-SaCas9 system (Supplemental Fig.…”

Section: In Vivo Genome Editing Using St1cas9mentioning

confidence: 53%

Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

et al. 2020

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Targeting definite genomic locations using CRISPR-Cas systems requires a set of enzymes with unique protospacer adjacent motif (PAM) compatibilities. To expand this repertoire, we engineered nucleases, cytosine base editors, and adenine base editors from the archetypal Streptococcus thermophilus CRISPR1-Cas9 (St1Cas9) system. We found that St1Cas9 strain variants enable targeting to five distinct A-rich PAMs and provide a structural basis for their specificities. The small size of this ortholog enables expression of the holoenzyme from a single adeno-associated viral vector for in vivo editing applications. Delivery of St1Cas9 to the neonatal liver efficiently rewired metabolic pathways, leading to phenotypic rescue in a mouse model of hereditary tyrosinemia. These robust enzymes expand and complement current editing platforms available for tailoring mammalian genomes.

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Section: In Vivo Genome Editing Using St1cas9mentioning

confidence: 53%

Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

et al. 2020

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“…AAV8 was included, since AAV-LK03 does not transduce murine cells (25). As described previously (59), the majority of the injected AAVs was found to target the liver when delivering the virus i.v. While AAV-KP1 appeared to transduce mouse liver more rapidly than AAV-DJ, expression levels were only slightly higher once steady state expression was achieved at later time points.…”

Section: Evaluation Of Transduction Efficiency Of the New Aav Variantmentioning

confidence: 99%

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

Pekrun¹,

Alencastro²,

Luo³

et al. 2019

JCI Insight

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Conflict of interest: KP and MAK are named on patent applications for AAV variants used in this paper. MAK has equity interests in LogicBio Therapeutics. MG has equity interests in Yecuris Corp., Ambys Medicines, and LogicBio Therapeutics. MH owns stock in Encellin and Viacyte Inc., receives research support from Eli Lily, and holds roles as consultant and member of the scientific advisory board for Semma Therapeutics and Encellin.

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“…AAV8 was included since AAV-LK03 does not transduce murine cells (Lisowski et al, 2014). As described previously (Palaschak et al, 2019), the majority of the injected AAVs was found to target the liver when delivering the virus intravenously.…”

Section: In Vivo Biodistribution Of the Aav-kp Variants In Micementioning

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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AAV-Mediated Gene Delivery to the Liver: Overview of Current Technologies and Methods

Cited by 24 publications

References 159 publications

Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

Versatile and robust genome editing with Streptococcus thermophilus CRISPR1-Cas9

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

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

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