scholarly journals Inducible scAAV2.GRE.MMP1 lowers IOP long-term in a large animal model for steroid-induced glaucoma gene therapy

Gene Therapy ◽  
2016 ◽  
Vol 23 (5) ◽  
pp. 438-449 ◽  
Author(s):  
T Borrás ◽  
L K Buie ◽  
M G Spiga
Keyword(s):  
Gene Therapy ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal

Acute, subacute, and long-term evaluation of a novel endovascular occlusion system in a large animal model

2014 ◽  
Vol 85 (6) ◽  
pp. 1026-1032 ◽  
Author(s):  
Anthony Venbrux ◽  
Philippe Gailloud ◽  
Martin G. Radvany ◽  
Leon Rudakov ◽  
Maximilian Y. Emmert ◽  
...  
Keyword(s):  
Animal Model ◽  
Large Animal Model ◽  
Large Animal ◽  
Endovascular Occlusion ◽  
Term Evaluation

scholarly journals 197Inhibition of TASK-1 by gene therapy and pharmacological compounds suppresses atrial fibrillation in a large animal model

2018 ◽  
Vol 39 (suppl_1) ◽  
Author(s):  
C Schmidt ◽  
F Wiedmann ◽  
C Beyersdorf ◽  
Z Zhao ◽  
I El-Battrawy ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Gene Therapy ◽  
Animal Model ◽  
Large Animal Model ◽  
Large Animal

Multi-Tissue, Long-Term Engraftment and Expansion of BCR-ABL-transduced Human Lin-CD34+ Cord Blood Cells in a Large Animal Model.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3265-3265
Author(s):  
Fanyi Zeng ◽  
Mei-Jue Chen ◽  
Zhi-Jian Gong ◽  
Don A. Baldwin ◽  
Hui Qian ◽  
...  
Keyword(s):  
Animal Model ◽  
Cord Blood ◽  
Hematopoietic Cells ◽  
In Utero ◽  
Human Cells ◽  
Laser Scanning Microscopy ◽  
Large Animal Model ◽  
Large Animal ◽  
Wbc Count

Abstract Abstract 3265 Poster Board III-1 In utero transplantation of large animals (sheep and goats) with human hematopoietic cells has proven valuable in distinguishing subsets of human cells with short- and long-term repopulating activity. Transplantation of secondary and tertiary fetal sheep with cells regenerated in primary sheep has also demonstrated the ability of human hematopoietic stem cells to retain and execute their self-renewal potential in a xenogeneic setting. We now describe the novel extension of this approach to the generation of a BCR-ABL gene transfer-based in vivo model of human myeloproliferative disease. Lin-CD34+ human cord blood (CB) cells were transduced with BCR-ABL retrovirus (MSCV-BCR-ABL-IRES-GFP) and the cells were then injected IP into pre-immune fetal goats at 45–55 days of gestation. This induced a high frequency of abortion among the injected fetuses: 79% (n=22) when >5×104BCR-ABL- transduced CB cells were injected as compared to 64% (n=9) when control (MIG)-transduced cells were injected. Six goats transplanted with 2×104 BCR-ABL-transduced cells were born alive and 3 weeks after birth, 3 of these were sacrificed so that their tissues could be analyzed. Interestingly, in the goats injected with BCR-ABL-transduced human cells, only GFP+(BCR-ABL+) human cells were detected and these were found in multiple hematopoietic and non-hematopoietic tissues, including peripheral blood, bone marrow (BM), liver, kidney, lung, heart, and skeletal and smooth muscle (1–49%) by fluorescence microscopy and confocal laser scanning microscopy, FISH and FACS. Immunohistochemical analysis allowed positive cells to also be detected in frozen sections of liver tissue. Continued follow-up of the other recipients of transduced cells showed that the 3 injected with BCR-ABL-transduced cells all developed features of early chronic phase human chronic myeloid leukemia (CML), as evidenced by a 3- to 5-fold elevation in their WBC count (up to 2.5×1010/L as compared to 5–8×109/L in the recipients of MIG-transduced cells, P<0.01). Changes in the WBC count were seen as early as 3 months after birth and up to 2.5 years post-transplant and were accompanied in all 3 of these goats by the presence of GFP+ cells, including human CD34+ stem/progenitor cells, in the blood and BM. Quantitative real-time PCR analysis of genomic DNA from multiple tissues demonstrated up to 8×104 copies of transgene per microgram of DNA. Microarray transcript profiling of blood and liver from BCR-ABL chimeric goats confirmed expression of many human genes, including 321 that were detected at >2.5-fold higher levels in the BCR-ABL chimeric goats as compared to both control chimeric goats and normal human CB. These over-expressed genes are from several functional categories, including tyrosine kinases and other proteins with phosphorylation activities, cell cycle control, cell adhesion, homing and differentiation, transcription, nucleotide binding and ion transport. Several were confirmed by quantitative RT-PCR. These results demonstrate long-term engraftment, but slow expansion of primitive human hematopoietic cells transduced with BCR-ABL fusion gene and transplanted in utero in a large animal model. This novel xenotransplant goat model should be useful for characterizing the early (pre-symptomatic) phase of human CML and for assessing new therapies with potential long-term benefits. Disclosures: No relevant conflicts of interest to declare.

Sustained phenotypic correction of hemophilia B dogs with a factor IX null mutation by liver-directed gene therapy

Blood ◽  
2002 ◽  
Vol 99 (8) ◽  
pp. 2670-2676 ◽  
Author(s):  
Jane D. Mount ◽  
Roland W. Herzog ◽  
D. Michael Tillson ◽  
Susan A. Goodman ◽  
Nancy Robinson ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Coagulation Factor ◽  
Factor Ix ◽  
Hemophilia B ◽  
Large Animal Model ◽  
Null Mutation ◽  
Large Animal ◽  
Adeno Associated Virus ◽  
Increased Risk

Abstract Hemophilia B is an X-linked coagulopathy caused by absence of functional coagulation factor IX (FIX). Using adeno-associated virus (AAV)–mediated, liver-directed gene therapy, we achieved long-term (&gt; 17 months) substantial correction of canine hemophilia B in 3 of 4 animals, including 2 dogs with an FIX null mutation. This was accomplished with a comparatively low dose of 1 × 1012 vector genomes/kg. Canine FIX (cFIX) levels rose to 5% to 12% of normal, high enough to result in nearly complete phenotypic correction of the disease. Activated clotting times and whole blood clotting times were normalized, activated partial thromboplastin times were substantially reduced, and anti-cFIX was not detected. The fourth animal, also a null mutation dog, showed transient expression (4 weeks), but subsequently developed neutralizing anti-cFIX (inhibitor). Previous work in the canine null mutation model has invariably resulted in inhibitor formation following treatment by either gene or protein replacement therapies. This study demonstrates that hepatic AAV gene transfer can result in sustained therapeutic expression in a large animal model characterized by increased risk of a neutralizing anti-FIX response.

scholarly journals TCT-825 In-Vivo Long Term Evaluation of a Novel Mitral Valve Regurgitation Therapy: Experience in a Preclinical Large Animal Model

2013 ◽  
Vol 62 (18) ◽  
pp. B249
Author(s):  
Athanasios Peppas ◽  
Jon Wilson ◽  
Yanping Cheng ◽  
Christopher Seguin ◽  
Masahiko Shibuya ◽  
...  
Keyword(s):  
Animal Model ◽  
Mitral Valve ◽  
Mitral Valve Regurgitation ◽  
Large Animal Model ◽  
Large Animal ◽  
Valve Regurgitation ◽  
Term Evaluation

scholarly journals Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

2015 ◽  
Vol 112 (43) ◽  
pp. E5844-E5853 ◽  
Author(s):  
William A. Beltran ◽  
Artur V. Cideciyan ◽  
Simone Iwabe ◽  
Malgorzata Swider ◽  
Mychajlo S. Kosyk ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinitis Pigmentosa ◽  
Large Animal Model ◽  
Therapeutic Window ◽  
Large Animal ◽  
Visual Behavior ◽  
Rate Of Progression ◽  
Photoreceptor Neurons ◽  
Retinal Gene Therapy

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the humanRPGRtransgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy ofRPGRgene augmentation and substantially broaden the therapeutic window for intervention in patients withRPGR-XLRP.

scholarly journals Long-term neuroretinal full-thickness transplants in a large animal model of severe retinitis pigmentosa

2006 ◽  
Vol 245 (6) ◽  
pp. 835-846 ◽  
Author(s):  
Fredrik Ghosh ◽  
Karl Engelsberg ◽  
Robert V. English ◽  
Robert M. Petters
Keyword(s):  
Animal Model ◽  
Retinitis Pigmentosa ◽  
Large Animal Model ◽  
Large Animal ◽  
Full Thickness

scholarly journals Cardiac AAV9-S100A1 Gene Therapy Rescues Post-Ischemic Heart Failure in a Preclinical Large Animal Model

2011 ◽  
Vol 3 (92) ◽  
pp. 92ra64-92ra64 ◽  
Author(s):  
S. T. Pleger ◽  
C. Shan ◽  
J. Ksienzyk ◽  
R. Bekeredjian ◽  
P. Boekstegers ◽  
...  
Keyword(s):  
Heart Failure ◽  
Gene Therapy ◽  
Animal Model ◽  
Ischemic Heart ◽  
Large Animal Model ◽  
Large Animal ◽  
Ischemic Heart Failure
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