scholarly journals Harnessing the Natural Biology of Adeno-Associated Virus to Enhance the Efficacy of Cancer Gene Therapy

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1205
Author(s):  
Jacquelyn J. Bower ◽  
Liujiang Song ◽  
Prabhakar Bastola ◽  
Matthew L. Hirsch
Keyword(s):  
Gene Therapy ◽  
Treatment Strategies ◽  
Cancer Gene Therapy ◽  
Current Treatment ◽  
Wild Type ◽  
Adeno Associated Virus ◽  
Pharmaceutical Development ◽  
Monogenic Diseases ◽  
Development Pipeline ◽  
Simian Adenovirus

Adeno-associated virus (AAV) was first characterized as small “defective” contaminant particles in a simian adenovirus preparation in 1965. Since then, a recombinant platform of AAV (rAAV) has become one of the leading candidates for gene therapy applications resulting in two FDA-approved treatments for rare monogenic diseases and many more currently in various phases of the pharmaceutical development pipeline. Herein, we summarize rAAV approaches for the treatment of diverse types of cancers and highlight the natural anti-oncogenic effects of wild-type AAV (wtAAV), including interactions with the cellular host machinery, that are of relevance to enhance current treatment strategies for cancer.

scholarly journals Cancer gene therapy using a novel adeno-associated virus vector expressing human wild-type p53

Gene Therapy ◽  
1997 ◽  
Vol 4 (7) ◽  
pp. 675-682 ◽  
Author(s):  
MH Qazilbash ◽  
X Xiao ◽  
P Seth ◽  
KH Cowan ◽  
CE Walsh
Keyword(s):  
Gene Therapy ◽  
Cancer Gene Therapy ◽  
Virus Vector ◽  
Cancer Gene ◽  
Wild Type ◽  
Adeno Associated Virus ◽  
Wild Type P53 ◽  
Human Wild Type

scholarly journals Adeno-associated virus Rep proteins antagonize phosphatase PP1 to counteract KAP1 repression of the latent viral genome

2018 ◽  
Vol 115 (15) ◽  
pp. E3529-E3538 ◽  
Author(s):  
Sarah Smith-Moore ◽  
Stuart J. D. Neil ◽  
Cornel Fraefel ◽  
R. Michael Linden ◽  
Mathieu Bollen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Helper Virus ◽  
Protein Phosphatase 1 ◽  
Wild Type ◽  
Fha Domain ◽  
Adeno Associated Virus ◽  
Histone 3 ◽  
Rep Proteins ◽  
Cellular Factors

Adeno-associated virus (AAV) is a small human Dependovirus whose low immunogenicity and capacity for long-term persistence have led to its widespread use as vector for gene therapy. Despite great recent successes in AAV-based gene therapy, further improvements in vector technology may be hindered by an inadequate understanding of various aspects of basic AAV biology. AAV is unique in that its replication is largely dependent on a helper virus and cellular factors. In the absence of helper virus coinfection, wild-type AAV establishes latency through mechanisms that are not yet fully understood. Challenging the currently held model for AAV latency, we show here that the corepressor Krüppel-associated box domain-associated protein 1 (KAP1) binds the latent AAV2 genome at the rep ORF, leading to trimethylation of AAV2-associated histone 3 lysine 9 and that the inactivation of KAP1 repression is necessary for AAV2 reactivation and replication. We identify a viral mechanism for the counteraction of KAP1 in which interference with the KAP1 phosphatase protein phosphatase 1 (PP1) by the AAV2 Rep proteins mediates enhanced phosphorylation of KAP1-S824 and thus relief from KAP1 repression. Furthermore, we show that this phenomenon involves recruitment of the NIPP1 (nuclear inhibitor of PP1)–PP1α holoenzyme to KAP1 in a manner dependent upon the NIPP1 FHA domain, identifying NIPP1 as an interaction partner for KAP1 and shedding light on the mechanism through which PP1 regulates cellular KAP1 activity.

scholarly journals Antiangiogenic cancer gene therapy by adeno-associated virus 2-mediated stable expression of the soluble FMS-like tyrosine kinase-1 receptor

2004 ◽  
Vol 12 (1) ◽  
pp. 26-34 ◽  
Author(s):  
Gandham Mahendra ◽  
Sanjay Kumar ◽  
Tatyana Isayeva ◽  
Parameshwar J Mahasreshti ◽  
David T Curiel ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tyrosine Kinase ◽  
Cancer Gene Therapy ◽  
Stable Expression ◽  
Cancer Gene ◽  
Adeno Associated Virus

scholarly journals Cancer gene therapy mediated by CTS1, a p53 derivative: Advantage over wild-type p53 in growth inhibition of human tumors overexpressing MDM2

2000 ◽  
Vol 7 (5) ◽  
pp. 789-798 ◽  
Author(s):  
Cécile Bougeret ◽  
Angela Virone-Oddos ◽  
Emmanuelle Adeline ◽  
Frédéric Lacroix ◽  
Céline Lefranc ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Growth Inhibition ◽  
Cancer Gene Therapy ◽  
Human Tumors ◽  
Cancer Gene ◽  
Wild Type ◽  
Wild Type P53

scholarly journals Adeno-associated virus (AAV) vectors in cancer gene therapy

2016 ◽  
Vol 240 ◽  
pp. 287-301 ◽  
Author(s):  
Jorge L. Santiago-Ortiz ◽  
David V. Schaffer
Keyword(s):  
Gene Therapy ◽  
Cancer Gene Therapy ◽  
Cancer Gene ◽  
Adeno Associated Virus

scholarly journals Systemic Cancer Gene Therapy Using Adeno-associated Virus Type 1 Vector Expressing MDA-7/IL24

2007 ◽  
Vol 15 (10) ◽  
pp. 1805-1811 ◽  
Author(s):  
Ichiro Tahara ◽  
Koichi Miyake ◽  
Hideki Hanawa ◽  
Toshiyuki Kurai ◽  
Yukihiko Hirai ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Virus Type ◽  
Cancer Gene Therapy ◽  
Cancer Gene ◽  
Adeno Associated Virus

scholarly journals Adeno-Associated Virus 2-Mediated Antiangiogenic Cancer Gene Therapy

2004 ◽  
Vol 64 (5) ◽  
pp. 1781-1787 ◽  
Author(s):  
Selvarangan Ponnazhagan ◽  
Gandham Mahendra ◽  
Sanjay Kumar ◽  
Denise R. Shaw ◽  
Cecil R. Stockard ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cancer Gene Therapy ◽  
Cancer Gene ◽  
Adeno Associated Virus

scholarly journals Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease

Neurosurgery ◽  
2013 ◽  
Vol 74 (1) ◽  
pp. 99-111 ◽  
Author(s):  
Christopher G. Janson ◽  
Liudmila G. Romanova ◽  
Paola Leone ◽  
Zhenhong Nan ◽  
Lalitha Belur ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Enzyme Activity ◽  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Wild Type ◽  
Adeno Associated Virus ◽  
Ipsilateral Hemisphere ◽  
Blood Brain ◽  
Viral Particles ◽  
Mps I

Abstract BACKGROUND: Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations. OBJECTIVE: To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks. METHODS: Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface. RESULTS: Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods. CONCLUSION: Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.

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