Liver-directed gene therapy results in long-term correction of progressive familial intrahepatic cholestasis type 3 in mice

Aronson, Sem J.; Bakker, Robert S.; Shi, Xiaoxia; Duijst, Suzanne; Bloemendaal, Lysbeth ten; Waart, Dirk R. de; Verheij, Joanne; Ronzitti, Giuseppe; Elferink, Ronald P.J. Oude; Beuers, Ulrich; Paulusma, Coen C.; Bosma, Piter J.

doi:10.1016/j.jhep.2019.03.021

Cited by 43 publications

(30 citation statements)

References 47 publications

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“…Of note, these drug effects examined in the polyneuropathy and carrageenan model appeared to persist unchanged for at least 6-7 weeks. Long term expression has been similarly noted in other gene therapy studies 57,[93][94][95] . Importantly, these effects were unaccompanied by any detectable adverse motor effects or changes in bladder function.…”

Section: In Vivo Spinal Na V 17 Knock Downsupporting

confidence: 63%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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One sentence summary:In situ epigenome engineering approach for genomically scarless, durable, and non-addictive management of pain. ABSTRACTCurrent treatments for chronic pain rely largely on opioids despite their unwanted side effects and risk of addiction. Genetic studies have identified in humans key targets pivotal to nociceptive processing, with the voltage-gated sodium channel, Na V 1.7 (SCN9A), being perhaps the most promising candidate for analgesic drug development.Specifically, a hereditary loss-of-function mutation in Na V 1.7 leads to insensitivity to pain without other neurodevelopmental alterations. However, the high sequence similarity between Na V subtypes has frustrated efforts to develop selective inhibitors. Here, we investigated targeted epigenetic repression of Na V 1.7 via genome engineering approaches based on clustered regularly interspaced short palindromic repeats (CRISPR)-dCas9 and zinc finger proteins as a potential treatment for chronic pain.Towards this end, we first optimized the efficiency of Na V 1.7 repression in vitro in Neuro2A cells, and then by the lumbar intrathecal route delivered both genomeengineering platforms via adeno-associated viruses (AAVs) to assess their effects in three mouse models of pain: carrageenan-induced inflammatory pain, paclitaxel-induced neuropathic pain and BzATP-induced pain. Our results demonstrate: one, effective repression of Na V 1.7 in lumbar dorsal root ganglia; two, reduced thermal hyperalgesia in the inflammatory state; three, decreased tactile allodynia in the neuropathic state; and four, no changes in normal motor function. We anticipate this genomically scarless and non-addictive pain amelioration approach enabling Long-lasting Analgesia via Targeted in vivo Epigenetic Repression of Nav1.7, a methodology we dub pain LATER, will have significant therapeutic potential, such as for preemptive administration in 2 anticipation of a pain stimulus (pre-operatively), or during an established chronic pain state.

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Section: In Vivo Spinal Na V 17 Knock Downsupporting

confidence: 63%

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Moreno

Catroli

Alemán

et al. 2019

Preprint

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“…Future medical therapies will include targeting various proteins involved in hepatocyte regulation and export or intestinal reuptake of BAs. Novel approaches to replacing the gene defect include hepatocyte transplantation of induced pluripotent stem cells and gene therapy . Another intriguing intervention that is currently being studied in animal models, and that could highly impact ALGS outcomes if successful, entails hepatocyte transdifferentiation into cholangiocytes, resulting in growth of functional intrahepatic bile ducts .…”

Section: Algsmentioning

confidence: 99%

“…Novel approaches to replacing the gene defect include hepatocyte transplantation of induced pluripotent stem cells and gene therapy. 11 Another intriguing intervention that is currently being studied in animal models, and that could highly impact ALGS outcomes if successful, entails hepatocyte transdifferentiation into cholangiocytes, resulting in growth of functional intrahepatic bile ducts. 12 The current revolution of genomics, organoid development, and personalized medicine signifies a bright future for inherited cholestatic diseases.…”

Section: An Official Learning Resource Of Aasldmentioning

confidence: 99%

Inherited Cholestatic Diseases in the Era of Personalized Medicine

Goldberg

Mack

2020

Clinical Liver Disease

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“…In order to further evaluate AAV-MDR3-Aco for efficacy in correcting the disease, we used a clinically relevant model of PFIC3 based on Abcb4 −/− mice with an FVB genetic background. Although this animal model presents more severe symptoms in females than males 10 , the disease is sufficiently severe in either sex not to necessitate dietary challenge in contrast to a different background strain that has been described by others 21 . We chose to treat 2-week-old Abcb4 −/− mice because young mice represent a more suitable model for PFIC3 therapy since this disease manifests in humans early in childhood.…”

Section: Discussionmentioning

confidence: 68%

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

Weber¹,

Odriozola

Martínez-García

et al. 2019

Nat Commun

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Progressive familial intrahepatic cholestasis type 3 (PFIC3) is a rare monogenic disease caused by mutations in the ABCB4 gene, resulting in a reduction in biliary phosphatidylcholine. Reduced biliary phosphatidylcholine cannot counteract the detergent effects of bile salts, leading to cholestasis, cholangitis, cirrhosis and ultimately liver failure. Here, we report results from treating two- or five-week-old Abcb4−/− mice with an AAV vector expressing human ABCB4, resulting in significant decreases of PFIC3 disease biomarkers. All male mice achieved a sustained therapeutic effect up through 12 weeks, but the effect was achieved in only 50% of females. However, two-week-old females receiving a second inoculation three weeks later maintained the therapeutic effect. Upon sacrifice, markers of PFIC3 disease such as, hepatosplenomegaly, biliary phosphatidylcholine and liver histology were significantly improved. Thus, AAV-mediated gene therapy successfully prevented PFIC3 symptoms in a clinically relevant mouse model, representing a step forward in improving potential therapy options for PFIC3 patients.

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Liver-directed gene therapy results in long-term correction of progressive familial intrahepatic cholestasis type 3 in mice

Cited by 43 publications

References 47 publications

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Long-lasting Analgesia via Targetedin vivoEpigenetic Repression of Nav1.7

Inherited Cholestatic Diseases in the Era of Personalized Medicine

Gene therapy for progressive familial intrahepatic cholestasis type 3 in a clinically relevant mouse model

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