In vivo laser targeted gene therapy of retina ganglion cells (Conference Presentation)

2019 ◽  
Author(s):  
Ariel Wilson ◽  
Javier Mazzaferri ◽  
Éric Bergeron ◽  
Sergiy Patskovsky ◽  
Paule Marcoux-Valiquette ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Ganglion Cells ◽  
Targeted Gene Therapy

scholarly journals Adenovirus-mediated hypoxia-targeted gene therapy using HSV thymidine kinase and bacterial nitroreductase prodrug-activating genes in vitro and in vivo

2011 ◽  
Vol 18 (11) ◽  
pp. 773-784 ◽  
Author(s):  
T J Harvey ◽  
I M Hennig ◽  
S D Shnyder ◽  
P A Cooper ◽  
N Ingram ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Thymidine Kinase ◽  
Targeted Gene Therapy ◽  
Hsv Thymidine Kinase

scholarly journals Restoring the natural tropism of AAV2 vectors for human liver

2020 ◽  
Vol 12 (560) ◽  
pp. eaba3312
Author(s):  
Marti Cabanes-Creus ◽  
Claus V. Hallwirth ◽  
Adrian Westhaus ◽  
Boaz H. Ng ◽  
Sophia H.Y. Liao ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tissue Culture ◽  
Human Liver ◽  
Xenograft Model ◽  
Human Hepatocytes ◽  
Targeted Gene Therapy ◽  
Tissue Culture Propagation ◽  
Made In

Recent clinical successes in gene therapy applications have intensified interest in using adeno-associated viruses (AAVs) as vectors for therapeutic gene delivery. Although prototypical AAV2 shows robust in vitro transduction of human hepatocyte–derived cell lines, it has not translated into an effective vector for liver-directed gene therapy in vivo. This is consistent with observations made in Fah−/−/Rag2−/−/Il2rg−/− (FRG) mice with humanized livers, showing that AAV2 functions poorly in this xenograft model. Here, we derived naturally hepatotropic AAV capsid sequences from primary human liver samples. We demonstrated that capsid mutations, likely acquired as an unintentional consequence of tissue culture propagation, attenuated the intrinsic human hepatic tropism of natural AAV2 and related human liver AAV isolates. These mutations resulted in amino acid changes that increased binding to heparan sulfate proteoglycan (HSPG), which has been regarded as the primary cellular receptor mediating AAV2 infection of human hepatocytes. Propagation of natural AAV variants in vitro showed tissue culture adaptation with resulting loss of tropism for human hepatocytes. In vivo readaptation of the prototypical AAV2 in FRG mice with a humanized liver resulted in restoration of the intrinsic hepatic tropism of AAV2 through decreased binding to HSPG. Our results challenge the notion that high affinity for HSPG is essential for AAV2 entry into human hepatocytes and suggest that natural AAV capsids of human liver origin are likely to be more effective for liver-targeted gene therapy applications than culture-adapted AAV2.

Abstract 2: Naked CanScript, an 18-base pair sequence, has tumor cell-specific promoter activity in vivo: Implications for targeted gene therapy

2010 ◽  
Author(s):  
Janet A. Sawicki ◽  
Yu-Hung Huang ◽  
Joseph Cozzitorto ◽  
Robert Langer ◽  
Daniel G. Anderson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Tumor Cell ◽  
Base Pair ◽  
Promoter Activity ◽  
Pair Sequence ◽  
Targeted Gene Therapy

scholarly journals Complement C3-targeted gene therapy restricts onset and progression of neurodegeneration in chronic mouse glaucoma

2018 ◽  
Author(s):  
Alejandra Bosco ◽  
Sarah R Anderson ◽  
Kevin T Breen ◽  
Cesar O Romero ◽  
Michael R Steele ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Complement Activation ◽  
Ganglion Cells ◽  
Therapeutic Benefit ◽  
Complement C3 ◽  
Retinal Ganglion ◽  
Intraocular Pressure Elevation ◽  
Targeted Gene Therapy ◽  
Disease Stages ◽  
The Complement System

ABSTRACTDysregulation of the complement system is implicated in neurodegeneration, including human and animal glaucoma. Optic nerve and retinal damage in glaucoma is preceded by local complement upregulation and activation, but whether targeting this early innate immune response could have therapeutic benefit remains undefined. Because complement signals through three pathways that intersect at complement C3 activation, here we targeted this step to restore complement balance in the glaucomatous retina, and to determine its contribution to degeneration onset and/or progression. To achieve this, we combined adeno-associated viral retinal gene therapy with the targeted C3 inhibitor CR2-Crry. We show that intravitreal injection of AAV2.CR2-Crry produced sustained Crry overexpression in the retina, and reduced deposition of the activation product complement C3d on retinal ganglion cells and the inner retina of DBA/2J mice. This resulted in neuroprotection of retinal ganglion cell axons and somata despite continued intraocular pressure elevation, suggesting a direct restriction of neurodegeneration onset and progression, and significant delay to terminal disease stages. Our study uncovers a damaging effect of complement C3 or downstream complement activation in glaucoma and establishes AAV2.CR2-Crry as a viable therapeutic strategy to target pathogenic C3-mediated complement activation in the glaucomatous retina.

scholarly journals Regeneration of pancreatic islets in vivo by ultrasound-targeted gene therapy

Gene Therapy ◽  
2010 ◽  
Vol 17 (11) ◽  
pp. 1411-1420 ◽  
Author(s):  
S Chen ◽  
M Shimoda ◽  
M-Y Wang ◽  
J Ding ◽  
H Noguchi ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Pancreatic Islets ◽  
Targeted Gene Therapy

scholarly journals Rad51 Promoter-Targeted Gene Therapy Is Effective for In Vivo Visualization and Treatment of Cancer

2012 ◽  
Vol 20 (2) ◽  
pp. 347-355 ◽  
Author(s):  
Christopher M Hine ◽  
Andrei Seluanov ◽  
Vera Gorbunova
Keyword(s):  
Gene Therapy ◽  
Targeted Gene Therapy ◽  
Rad51 Promoter
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