The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice

Hordeaux, Juliette; Wang, Qiang; Katz, Nathan; Buza, Elizabeth L.; Bell, Peter; Wilson, James M.

doi:10.1016/j.ymthe.2018.01.018

Cited by 338 publications

(343 citation statements)

References 12 publications

Supporting

Mentioning

329

Contrasting

Order By: Relevance

“…Another example, where results from rodent studies do not translate directly to studies with large animal models, is the recent observation that high doses (2e14 GC/kg) of rAAV9 vectors can lead to severe acute toxicity in piglets and non-human primates when delivered intravenously [91,92]. In this case, and different from the trial results reported by Manno et al [59], the toxicity was likely due to an acute, innate immune response (around 5 days after vector administration).…”

Section: Lessons Learned From Ex-vivo Successmentioning

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

View full text Add to dashboard Cite

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.

show abstract

Section: Lessons Learned From Ex-vivo Successmentioning

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

View full text Add to dashboard Cite

show abstract

“…26 These promising achievements may allow the administration of reduced dose of vector for a similar efficacy; this may address recent concerns over possible doselimited toxicity of AAV9-derived capsids. 27,28 Fetal gene therapy has remained an elusive goal for decades. This proof of concept study highlights long-term efficacy and technical feasibility of this approach.…”

mentioning

confidence: 99%

Fetal gene therapy for neurodegenerative lysosomal storage diseases

Baruteau

Waddington

2019

J of Inher Metab Disea

View full text Add to dashboard Cite

“…Interestingly, this receptor is not conserved in primates and humans, thus implying species-specific difference in the transduction efficacy of these capsids. On this line, new findings indicate that brain transduction in adult primates is not improved with PHP.B compared to AAV9 although only few animals have yet been tested 38,39 . Nonetheless, the PHP.B/eB receptor belongs to the large family of Ly6/uPar proteins, some of which are conserved in mammalian evolution and can be found in human brain endothelium, representing valuable targets for capsid engineering 40,41 .…”

Section: Discussionmentioning

confidence: 99%

Whole brain delivery of an instability-proneMecp2transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

Luoni

Giannelli

Indrigo

et al. 2019

Preprint

View full text Add to dashboard Cite

Rett syndrome (RTT) is an incurable neurodevelopmental disorder caused by mutations inthe gene encoding for methyl-CpG binding-protein 2 (MeCP2). Gene therapy for this disease presents inherent hurdles since MECP2 is expressed throughout the brain and its duplication leads to severe neurological conditions as well. However, the recent introduction of AAV-PHP.eB, an engineered capsid with an unprecedented efficiency in crossing the blood-brain barrier upon intravenous injection, has provided an invaluable vehicle for gene transfer in the mouse nervous system. Herein, we use AAV-PHP.eB to deliver an instability-prone Mecp2 (iMecp2) transgene cassette which, increasing RNA destabilization and inefficient protein translation of the viral Mecp2 transgene, limits supraphysiological Mecp2 protein levels in transduced neural tissues. Intravenous injections of the PHP.eB-iMecp2 virus in symptomatic male and female Mecp2 mutant mice significantly ameliorated the disease progression with improved locomotor activity, coordination, lifespan and normalization of altered gene expression and mTOR signaling. Remarkably, PHP.eB-iMecp2 administration did not result in severe toxicity effects either in female Mecp2 mutant or in wild-type animals. In contrast, we observed a strong immune response to the transgene in treated male Mecp2 mutant mice that was overcome by immunosuppression. Overall, PHP.eB-mediated delivery of the iMecp2 cassette provided widespread and efficient gene transfer maintaining physiological Mecp2 protein levels in the brain. This combination defines a novel viral system with significant therapeutic efficacy and increased safety which can contribute to overcome the hurdles that are delaying clinical applications of gene therapy for RTT. One Sentence Summary: Global brain transduction of the instability-prone Mecp2 transgene by systemic AAV-PHP.eB administration is both safe and effective in protecting male and female Mecp2 mutant mice from the RTT disease phenotype. WT KO -GFP KO-iMeCP2-10 11 vg 4 8 12 16 20 24 28 32 36 40 0 50 100 Weeks Percent survival WT KO-GFP KO-iMecp2-10 11 vg KO-iMecp2-10 11 vg + Csa KO-GFP +Csa

show abstract

The Neurotropic Properties of AAV-PHP.B Are Limited to C57BL/6J Mice

Cited by 338 publications

References 12 publications

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

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

Fetal gene therapy for neurodegenerative lysosomal storage diseases

Whole brain delivery of an instability-proneMecp2transgene improves behavioral and molecular pathological defects in mouse models of Rett syndrome

Contact Info

Product

Resources

About