Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice

Quirin, Kayla; Kwon, Jason J.; Alioufi, Arafat; Factora, Tricia D.; Temm, Constance J.; Jacobsen, Max; Sandusky, George E.; Shontz, Kim; Chicoine, Louis G.; Clark, K. Reed; Mendell, Joshua T.; Korc, Murray; Kota, Janaiah

doi:10.1016/j.omtm.2017.09.006

Cited by 25 publications

(19 citation statements)

References 93 publications

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“…Our study shows that AAV-9-mediated miR-155 delivery was efficient in the pancreas, and the expression of the target gene TAB2 was visibly regulated. Among AAV serotypes, AAV-9 showed more efficient pancreatic delivery in vivo, mediating long-term transgene expression with no immune response 35,36 . Thus, we compared the effect of miR-155 in the cerulein AP model with that in the cerulein plus LPS or L-arginine model.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model

et al. 2019

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Acute pancreatitis (AP) is a common digestive disease characterized by inflammation of the pancreas. MiR-155 plays a role in promoting inflammation and inhibiting the activation of anti-inflammatory pathways. Impaired autophagy could promote zymogen activation, abnormal acinar cell secretion, cell death, and the inflammatory response to aggravate AP. The aim of this study was to ascertain the effect of silencing miR-155 on AP through its effects on inflammation and impaired autophagy in vivo. In this study, AAV(adeno-associated virus)-mediated miR-155 and miR-155 sponge were injected through the tail vein of mice. After 3 weeks, AP was induced by intraperitoneal (IP) injections of cerulein. Pancreatic and pulmonary tissues were analyzed after 24 h. Silencing of miR-155 ameliorated pancreas and lung damage in three AP models of mice by preventing accumulation of autophagosomes that are unable to fuse with lysosomes and decreasing pancreatic inflammation by targeting TAB2. 3-MA could reduce the aberrant accumulation of autophagosomes, which alleviates the pancreas damage that was aggravated by increasing miR-155 levels. These findings demonstrate that the inhibition of miR-155 holds promise for limiting pancreatitis.

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Section: Discussionmentioning

confidence: 99%

Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model

et al. 2019

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“…Although the novel vectors described in this study mainly transduced the liver when delivered systemically, they could possibly be safely delivered in close proximity to islets using endoscopic retrograde cholangio-pancreatography (ERCP), a procedure that is routinely used in patients to examine the pancreatic and bile ducts (Hibberts & Barnes, 2003). Several recent studies have reported retrograde pancreatic intraductal delivery for safe and effective administration of rAAV vectors into the pancreas of mice (Jimenez et al, 2011;Mallol et al, 2017;Quirin et al, 2018). The vectors generated in our study could be used for gene therapy of diabetes by delivering transcription factors or small hairpin RNAs (shRNA) into pancreatic islet cells.…”

Section: Discussionmentioning

confidence: 96%

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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“…For in vivo gene editing, AAVs are currently the leading candidates for virus-based gene manipulation because of their broad tissue tropism, non-pathogenic nature, and low immunogenicity [30]. Although AAV6 exhibited high pancreatic tropism [31], we applied AAV2 for in vivo CRISPR delivery to establish animal model for early stage neoplasia development.…”

Section: Discussionmentioning

confidence: 99%

In vivo multiplex gene targeting with Streptococcus pyogens and Campylobacter jejuni Cas9 for pancreatic cancer modeling in wild-type animal

et al. 2020

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Pancreatic ductal adenocarcinoma is a lethal cancer type that is associated with multiple gene mutations in somatic cells. Genetically engineered mouse is hardly applicable for developing a pancreatic cancer model, and the xenograft model poses a limitation in the reflection of early stage pancreatic cancer. Thus, in vivo somatic cell gene engineering with clustered regularly interspaced short palindromic repeats is drawing increasing attention for generating an animal model of pancreatic cancer. In this study, we selected Kras, Trp53, Ink4a, Smad4, and Brca2 as target genes, and applied Campylobacter jejuni Cas9 (CjCas9) and Streptococcus pyogens Cas9 (SpCas9) for developing pancreatic cancer using adeno associated virus (AAV) transduction. After confirming multifocal and diffuse transduction of AAV2, we generated SpCas9 overexpression mice, which exhibited high double-strand DNA breakage (DSB) in target genes and pancreatic intraepithelial neoplasia (PanIN) lesions with two AAV transductions; however, wild-type (WT) mice with three AAV transductions did not develop PanIN. Furthermore, small-sized Cjcas9 was applied to WT mice with two AAV system, which, in addition, developed high extensive DSB and PanIN lesions. Histological changes and expression of cancer markers such as Ki67, cytokeratin, Mucin5a, alpha smooth muscle actin in duct and islet cells were observed. In addition, the study revealed several findings such as 1) multiple DSB potential of AAV-CjCas9, 2) peri-ductal lymphocyte infiltration, 3) multi-focal cancer marker expression, and 4) requirement of > 12 months for initiation of PanIN in AAV mediated targeting. In this study, we present a useful tool for in vivo cancer modeling that would be applicable for other disease models as well.

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Safety and Efficacy of AAV Retrograde Pancreatic Ductal Gene Delivery in Normal and Pancreatic Cancer Mice

Cited by 25 publications

References 93 publications

Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model

Inhibition of miR-155 reduces impaired autophagy and improves prognosis in an experimental pancreatitis mouse model

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

In vivo multiplex gene targeting with Streptococcus pyogens and Campylobacter jejuni Cas9 for pancreatic cancer modeling in wild-type animal

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