Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity

Paulk, Nicole K.; Pekrun, Katja; Zhu, Erhua; Nygaard, Sean; Li, Bin; Xu, Jianpeng; Chu, Kirk; Leborgne, Christian; Dane, Allison; Haft, Annelise; Zhang, Yue; Zhang, Feijie; Morton, Chris; Valentine, Marcus B.; Davidoff, Andrew M.; Nathwani, Amit C.; Mingozzi, Federico; Grompe, Markus; Alexander, Ian E.; Lisowski, Leszek; Kay, Mark A.

doi:10.1016/j.ymthe.2017.09.021

Cited by 144 publications

(164 citation statements)

References 59 publications

(84 reference statements)

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“…We compared the AAV serotypes with AAV8, the best-characterized serotype for liver transduction in humans (11, 43). Three serotypes—AAV3B (44), AAVLK03 (45), and the newly developed serotype AAVNP59 (46)—showed improved transduction efficiency (Fig. 8, D and E), with AAVLK03 showing significantly higher transgene expression compared to AAV8 in human primary hepatocytes (* P < 0.05, AAVLK03 compared to AAV8; Fig.…”

Section: Resultsmentioning

confidence: 98%

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

et al. 2017

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Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes. Then, we used adeno-associated virus (AAV) vectors optimized for hepatic expression to deliver the GAA transgenes to Gaa knockout (Gaa−/−) mice, a model of Pompe disease. Therapeutic gene transfer to the liver rescued glycogen accumulation in muscle and the central nervous system, and ameliorated cardiac hypertrophy as well as muscle and respiratory dysfunction in the Gaa−/− mice; mouse survival was also increased. Secretable GAA showed improved therapeutic efficacy and lower immunogenicity compared to nonengineered GAA. Scale-up to nonhuman primates, and modeling of GAA expression in primary human hepatocytes using hepatotropic AAV vectors, demonstrated the therapeutic potential of AAV vector–mediated liver expression of secretable GAA for treating pathological glycogen accumulation in multiple tissues in Pompe disease.

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Section: Resultsmentioning

confidence: 98%

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

et al. 2017

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“…Thus, the relative dosage ratio of transposon to transposase virions, which herein was based on our previous published work in other mouse models, could be further optimized to maximize transposition efficiency. This will also be aided by the ongoing development of highly human liver tropic capsids, such as LK03 and NP59 …”

Section: Discussionmentioning

confidence: 99%

“…This vector system possesses several properties that make it ideally suited to liver gene transfer. These include the ability to transduce nondividing cells such as quiescent hepatocytes, and a low propensity to induce liver inflammation and high tropism of selected serotypes for primary human hepatocytes in vivo . Therapeutic promise in the liver is exemplified by multiyear therapeutic efficacy following a single infusion of rAAV‐expressing Factor IX in hepatocytes of adult patients with severe hemophilia B …”

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confidence: 99%

Prevention of Cholestatic Liver Disease and Reduced Tumorigenicity in a Murine Model of PFIC Type 3 Using Hybrid AAV‐piggyBac Gene Therapy

et al. 2019

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Recombinant adeno‐associated viral (rAAV) vectors are highly promising vehicles for liver‐targeted gene transfer, with therapeutic efficacy demonstrated in preclinical models and clinical trials. Progressive familial intrahepatic cholestasis type 3 (PFIC3), an inherited juvenile‐onset, cholestatic liver disease caused by homozygous mutation of the ABCB4 gene, may be a promising candidate for rAAV‐mediated liver‐targeted gene therapy. The Abcb4‐/‐ mice model of PFIC3, with juvenile mice developing progressive cholestatic liver injury due to impaired biliary phosphatidylcholine excretion, resulted in cirrhosis and liver malignancy. Using a conventional rAAV strategy, we observed markedly blunted rAAV transduction in adult Abcb4‐/‐ mice with established liver disease, but not in disease‐free, wild‐type adults or in homozygous juveniles prior to liver disease onset. However, delivery of predominantly nonintegrating rAAV vectors to juvenile mice results in loss of persistent transgene expression due to hepatocyte proliferation in the growing liver. Conclusion: A hybrid vector system, combining the high transduction efficiency of rAAV with piggyBac transposase‐mediated somatic integration, was developed to facilitate stable human ABCB4 expression in vivo and to correct juvenile‐onset chronic liver disease in a murine model of PFIC3. A single dose of hybrid vector at birth led to life‐long restoration of bile composition, prevention of biliary cirrhosis, and a substantial reduction in tumorigenesis. This powerful hybrid rAAV‐piggyBac transposon vector strategy has the capacity to mediate lifelong phenotype correction and reduce the tumorigenicity of progressive familial intrahepatic cholestasis type 3 and, with further refinement, the potential for human clinical translation.

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“…This limitation makes it difficult to extrapolate non-clinical data to the clinic, especially if cumbersome and expensive humanized mice are not widely available. This has prompted others to consider human liver organoids as a possible intermediate step or substitute tissue for capsid selection [64]. …”

Section: A Brief History Of In-vivo Gene Therapymentioning

confidence: 99%

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

Haasteren

Hyde

Gill

2018

Expert Opinion on Biological Therapy

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Introduction: Ex-vivo gene therapy has had significant clinical impact over the last couple of years and in-vivo gene therapy products are being approved for clinical use. Gene therapy and gene editing approaches have huge potential to treat genetic disease and chronic illness. Areas covered: This article provides a review of in-vivo approaches for gene therapy in the lung and liver, exploiting non-viral and viral vectors with varying serotypes and pseudotypes to target-specific cells. Antibody responses inhibiting viral vectors continue to constrain effective repeat administration. Lessons learned from ex-vivo gene therapy and genome editing are also discussed. Expert opinion: The fields of lung and liver in-vivo gene therapy are thriving and a comparison highlights obstacles and opportunities for both. Overcoming immunological issues associated with repeated administration of viral vectors remains a key challenge. The addition of targeted small molecules in combination with viral vectors may offer one solution. A substantial bottleneck to the widespread adoption of in-vivo gene therapy is how to ensure sufficient capacity for clinical-grade vector production. In the future, the exploitation of gene editing approaches for in-vivo disease treatment may facilitate the resurgence of non-viral gene transfer approaches, which tend to be eclipsed by more efficient viral vectors.

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Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity

Cited by 144 publications

References 59 publications

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase

Prevention of Cholestatic Liver Disease and Reduced Tumorigenicity in a Murine Model of PFIC Type 3 Using Hybrid AAV‐piggyBac Gene Therapy

Lessons learned from lung and liver in-vivo gene therapy: implications for the future

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