New and improved AAVenues: current status of hemophilia B gene therapy

Brimble, Mark A.; Reiss, Ulrike; Nathwani, Amit C.; Davidoff, Andrew M.

doi:10.1517/14712598.2015.1106475

Cited by 20 publications

(19 citation statements)

References 92 publications

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“…Recombinant adeno‐associated virus (rAAV) vectors are considered as delivery vehicle of choice for liver‐directed gene therapy due to their strong natural tropism for this organ and excellent safety profile . They are derived from adeno‐associated viruses (AAVs), replication‐deficient parvoviruses with a single‐stranded DNA genome (4.7 kb) and a nonenveloped protein capsid (∼20 nm in diameter) that triggers cell infection and defines AAV postentry processing …”

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confidence: 99%

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Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors

et al. 2017

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Use of adeno‐associated viral (AAV) vectors for liver‐directed gene therapy has shown considerable success, particularly in patients with severe hemophilia B. However, the high vector doses required to reach therapeutic levels of transgene expression caused liver inflammation in some patients that selectively destroyed transduced hepatocytes. We hypothesized that such detrimental immune responses can be avoided by enhancing the efficacy of AAV vectors in hepatocytes. Because autophagy is a key liver response to environmental stresses, we characterized the impact of hepatic autophagy on AAV infection. We found that AAV induced mammalian target of rapamycin (mTOR)–dependent autophagy in human hepatocytes. This cell response was critically required for efficient transduction because under conditions of impaired autophagy (pharmacological inhibition, small interfering RNA knockdown of autophagic proteins, or suppression by food intake), recombinant AAV‐mediated transgene expression was markedly reduced, both in vitro and in vivo. Taking advantage of this dependence, we employed pharmacological inducers of autophagy to increase the level of autophagy. This resulted in greatly improved transduction efficiency of AAV vectors in human and mouse hepatocytes independent of the transgene, driving promoter, or AAV serotype and was subsequently confirmed in vivo. Specifically, short‐term treatment with a single dose of torin 1 significantly increased vector‐mediated hepatic expression of erythropoietin in C57BL/6 mice. Similarly, coadministration of rapamycin with AAV vectors resulted in markedly enhanced expression of human acid‐α‐glucosidase in nonhuman primates. Conclusion: We identified autophagy as a pivotal cell response determining the efficiency of AAVs intracellular processing in hepatocytes and thus the outcome of liver‐directed gene therapy using AAV vectors and showed in a proof‐of‐principle study how this virus–host interaction can be employed to enhance efficacy of this vector system. (Hepatology 2017;66:252–265).

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confidence: 99%

“…Among gene therapy clinical trials for liver‐related diseases, those for hemophilia B show the most promising results, with long‐term transgene expression of factor IX from rAAV‐transduced hepatocytes leading to restored blood coagulation. The high vector doses required to reach therapeutic expression levels, however, pose a continuous challenge .…”

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confidence: 99%

Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors

et al. 2017

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“…Clinicians must adapt replacement therapy to a wide range of phenotypic and pharmacokinetic variability. Long-term follow-up data with current approaches has been limited to [25][26][27][28][29][30] years but have shown that annualized bleeding rates are not zero and joint disease still appears in young adults. 13,14 Thus, what are the implications over a lifetime?…”

Section: What Are the Remaining Unmet Needs?mentioning

confidence: 99%

“…Each of these can target the liver and have their distinct advantages and disadvantages (see reviews). Adeno‐associated virus (AAV) is a nonenveloped parvovirus that was discovered as an accompanying virion to adenovirus infection, shows widespread infection in the human population, and yet is not associated with any pathogenic disease . Wild‐type AAV contains overlapping genes that encode the replication (r ep ) and capsid ( cap ) proteins between two inverted terminal repeats (ITRs).…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for hemophilia

Pipe

2017

Pediatric Blood & Cancer

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Individuals with the inherited bleeding disorder hemophilia have achieved tremendous advances in clinical outcomes through widespread implementation of prophylactic replacement with safe and efficacious factor VIII and IX. However, despite this therapeutic approach, bleeds still occur, some with serious consequence, joint disease has not been eradicated, and patients have not yet been liberated from the need for regular intravenous infusions. The shift from protein replacement to gene replacement is offering great hope to achieve durable levels of plasma factor activity levels high enough to remove the risk for recurrent joint bleeding. For the first time, clinical trial results are showing promise for "curative" correction of the bleeding phenotype.

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“…AAV vectors have thus been produced by transfection of three separate plasmids each containing one of these attributes: ITRs flanking the therapeutic gene cassette, rep/ cap genes or essential helper genes [50,51]. AAV has been shown to induce long-term transgene expression in a variety of tissues; thus, it has been actively explored for the treatment of genetic and acquired diseases, such as cystic fibrosis, hemophilia, Parkinson's disease and muscular dystrophy [52][53][54][55]. Although AAV-mediated gene therapy is efficient in tissues of varying origin, the most efficient transduction has been reported in skeletal muscle in vivo [52,56].…”

Section: Adeno-associated Virusmentioning

confidence: 99%

Evolving Lessons on Nanomaterial-Coated Viral Vectors for Local and Systemic Gene Therapy

Kasala

Yoon

Hong

et al. 2016

Nanomedicine (Lond.)

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Viral vectors are promising gene carriers for cancer therapy. However, virus-mediated gene therapies have demonstrated insufficient therapeutic efficacy in clinical trials due to rapid dissemination to nontarget tissues and to the immunogenicity of viral vectors, resulting in poor retention at the disease locus and induction of adverse inflammatory responses in patients. Further, the limited tropism of viral vectors prevents efficient gene delivery to target tissues. In this regard, modification of the viral surface with nanomaterials is a promising strategy to augment vector accumulation at the target tissue, circumvent the host immune response, and avoid nonspecific interactions with the reticuloendothelial system or serum complement. In the present review, we discuss various chemical modification strategies to enhance the therapeutic efficacy of viral vectors delivered either locally or systemically. We conclude by highlighting the salient features of various nanomaterial-coated viral vectors and their prospects and directions for future research.

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New and improved AAVenues: current status of hemophilia B gene therapy

Cited by 20 publications

References 92 publications

Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors

Autophagy determines efficiency of liver‐directed gene therapy with adeno‐associated viral vectors

Gene therapy for hemophilia

Evolving Lessons on Nanomaterial-Coated Viral Vectors for Local and Systemic Gene Therapy

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