Epidermal growth factor receptor is a co-receptor for adeno-associated virus serotype 6

Weller, Melodie L.; Amornphimoltham, Panomwat; Schmidt, M; Wilson, Paul; Gutkind, J. Silvio; Chiorini, John A.

doi:10.1038/nm.2145

Cited by 114 publications

(88 citation statements)

References 16 publications

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“…The approach is very robust and can allow the direct comparison of datasets collected from divergent platforms, such as microarrays, kinase assays, and drug toxicity profiles. Previous work with COMPARE has identified novel correlations between viruses and cellular receptors, multidrug resistance-1 expression, and rhodamine efflux, as well as mutant alleles of the RAS oncogene and sensitivity to cytosine arabinoside and topoisomerase II inhibitors (24)(25)(26)(27). Our study provides the first evidence, to our knowledge, of an association between BMP6 and AQP5 expression in both patients with pSS and a mouse model of pSS, and proposes a physiological mechanism for the loss of gland activity associated with this disease.…”

Section: Discussionmentioning

confidence: 99%

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Lai

Yin

Cabrera-Pérez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease that is estimated to affect 35 million people worldwide. Currently, no effective treatments exist for Sjögren’s syndrome, and there is a limited understanding of the physiological mechanisms associated with xerostomia and hyposalivation. The present work revealed that aquaporin 5 expression, a water channel critical for salivary gland fluid secretion, is regulated by bone morphogenetic protein 6. Increased expression of this cytokine is strongly associated with the most common symptom of primary Sjögren’s syndrome, the loss of salivary gland function. This finding led us to develop a therapy in the treatment of Sjögren’s syndrome by increasing the water permeability of the gland to restore saliva flow. Our study demonstrates that the targeted increase of gland permeability not only resulted in the restoration of secretory gland function but also resolved the hallmark salivary gland inflammation and systemic inflammation associated with disease. Secretory function also increased in the lacrimal gland, suggesting this local therapy could treat the systemic symptoms associated with primary Sjögren’s syndrome.

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Section: Discussionmentioning

confidence: 99%

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Lai

Yin

Cabrera-Pérez

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…This scenario is unique and does not appear to be the case for other AAV serotypes that recognize N-linked sialic acid. For instance, platelet-derived growth factor receptor (PDGFR) and epidermal growth factor receptor (EGFR) have been identified as coreceptors for AAV5 and AAV6, respectively (42,43). However, a putative coreceptor involved in the cellular uptake of AAV4 has yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Multiple Roles for Sialylated Glycans in Determining the Cardiopulmonary Tropism of Adeno-Associated Virus 4

Shen

Troupes

Pulicherla

et al. 2013

J Virol

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Adeno-associated virus 4 (AAV4) is one of the most divergent serotypes among known AAV isolates. Mucins or O-linked sialoglycans have been identified as the primary attachment receptors for AAV4 in vitro. However, little is known about the role(s) played by sialic acid interactions in determining AAV4 tissue tropism in vivo. In the current study, we first characterized two loss-of-function mutants obtained by screening a randomly mutated AAV4 capsid library. Both mutants harbored several amino acid residue changes localized to the 3-fold icosahedral symmetry axes on the AAV4 capsid and displayed low transduction efficiency in vitro. This defect was attributed to decreased cell surface binding as well as uptake of mutant virions. These results were further corroborated by low transgene expression and recovery of mutant viral genomes in cardiac and lung tissue following intravenous administration in mice. Pharmacokinetic analysis revealed rapid clearance of AAV4 mutants from the blood circulation in conjunction with low hemagglutination potential ex vivo. These results were recapitulated with mice pretreated intravenously with sialidase, directly confirming the role of sialic acids in determining AAV4 tissue tropism. Taken together, our results support the notion that blood-borne AAV4 particles interact sequentially with O-linked sialoglycans expressed abundantly on erythrocytes followed by cardiopulmonary tissues and subsequently for viral cell entry.

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“…Thus, it is possible that AAV-5 vector has high tissue tropism for male gonadal tissue and that the vector dissemination to the semen is minimized. Recently, the epidermal growth factor receptor was identified as a co-receptor for AAV-6 (Weller et al, 2010). These receptors are commonly found in several anatomic structures of the genitorurinary tract of mammals as well as in human spermatozoa (Damjanov et al, 1993;Oliva-Hernandez and Perez-Gutierrez, 2008).…”

Section: Efficacy and Safety Of Aav-5 And Aav-6 In Rabbitsmentioning

confidence: 99%

Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-Associated Virus (AAV)-5 and AAV-6 in a Large Animal Model

et al. 2011

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Intravascular delivery of adeno-associated virus (AAV) vector is commonly used for liver-directed gene therapy. In humans, the high prevalence of neutralizing antibodies to AAV-2 capsid and the wide cross-reactivity with other serotypes hamper vector transduction efficacy. Moreover, the safety of gene-based approaches depends on vector biodistribution, vector dose, and route of administration. Here we sought to characterize the safety of AAV-5 and AAV-6 for liver-mediated human factor IX (hFIX) expression in rabbits at doses of 1Â10 12 or 1Â10 13 viral genomes/kg. Circulating therapeutic levels of FIX were observed in both cohorts of AAV-6-hFIX, whereas for AAV-5-hFIX only the high dose was effective. Long-lasting inhibitory antibodies to hFIX were detected in three of the 10 AAV-6-injected animals but were absent in the AAV-5 group. Overall, vector shedding in the semen was transient and vector dose-dependent. However, the kinetics of clearance were remarkably faster for AAV-5 (3-5 weeks) compared with AAV-6 (10-13 weeks). AAV-6 vector sequences outside the liver were minimal at 20-30 weeks post-injection. In contrast, AAV-5 exhibited relatively high amounts of vector DNA in tissues other than the liver. Together these data are useful to further define the safety and potential for clinical translation of these AAV vectors.

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Epidermal growth factor receptor is a co-receptor for adeno-associated virus serotype 6

Cited by 114 publications

References 16 publications

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Aquaporin gene therapy corrects Sjögren’s syndrome phenotype in mice

Multiple Roles for Sialylated Glycans in Determining the Cardiopulmonary Tropism of Adeno-Associated Virus 4

Safety of Liver Gene Transfer Following Peripheral Intravascular Delivery of Adeno-Associated Virus (AAV)-5 and AAV-6 in a Large Animal Model

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