Adeno-Associated Virus-Mediated Rhodopsin Replacement Provides Therapeutic Benefit in Mice with a Targeted Disruption of the Rhodopsin Gene

2010 ◽  
Vol 21 (3) ◽  
pp. 311-323 ◽  
Author(s):  
Arpad Palfi ◽  
Sophia Millington-Ward ◽  
Naomi Chadderton ◽  
Mary O'Reilly ◽  
Tobias Goldmann ◽  
...  
Keyword(s):  
Therapeutic Benefit ◽  
Targeted Disruption ◽  
Adeno Associated Virus ◽  
Rhodopsin Gene

Retinopathy induced in mice by targeted disruption of the rhodopsin gene

1997 ◽  
Vol 15 (2) ◽  
pp. 216-219 ◽  
Author(s):  
Marian M. Humphries ◽  
Derrick Rancourt ◽  
G. Jane Farrar ◽  
Paul Kenna ◽  
Mark Hazel ◽  
...  
Keyword(s):  
Targeted Disruption ◽  
Rhodopsin Gene

scholarly journals Enhancement of Muscle Gene Delivery with Pseudotyped Adeno-Associated Virus Type 5 Correlates with Myoblast Differentiation

2001 ◽  
Vol 75 (16) ◽  
pp. 7662-7671 ◽  
Author(s):  
Dongsheng Duan ◽  
Ziying Yan ◽  
Yongping Yue ◽  
Wei Ding ◽  
John F. Engelhardt
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Gene Delivery ◽  
Muscle Cells ◽  
Therapeutic Benefit ◽  
Transduction Efficiency ◽  
Great Promise ◽  
Adeno Associated Virus ◽  
Muscle Gene ◽  
Duchenne's Muscular Dystrophy

ABSTRACT Adeno-associated virus (AAV)-based muscle gene therapy has achieved tremendous success in numerous animal models of human diseases. Recent clinical trials with this vector have also demonstrated great promise. However, to achieve therapeutic benefit in patients, large inocula of virus will likely be necessary to establish the required level of transgene expression. For these reasons, efforts aimed at increasing the efficacy of AAV-mediated gene delivery to muscle have the potential for improving the safety and therapeutic benefit in clinical trials. In the present study, we compared the efficiency of gene delivery to mouse muscle cells for recombinant AAV type 2 (rAAV-2) and rAAV-2cap5 (AAV-2 genomes pseudo-packaged into AAV-5 capsids). Despite similar levels of transduction by these two vectors in undifferentiated myoblasts, pseudotyped rAAV-2cap5 demonstrated dramatically enhanced transduction in differentiated myocytes in vitro (>500-fold) and in skeletal muscle in vivo (>200-fold) compared to rAAV-2. Serotype-specific differences in transduction efficiency did not directly correlate with viral binding to muscle cells but rather appeared to involve endocytic or intracellular barriers to infection. Furthermore, application of this pseudotyped virus in a mouse model of Duchenne's muscular dystrophy also demonstrated significantly improved transduction efficiency. These findings should have a significant impact on improving rAAV-mediated gene therapy in muscle.

scholarly journals Allele-Specific Silencing of MutantMyh6Transcripts in Mice Suppresses Hypertrophic Cardiomyopathy

Science ◽  
2013 ◽  
Vol 342 (6154) ◽  
pp. 111-114 ◽  
Author(s):  
Jianming Jiang ◽  
Hiroko Wakimoto ◽  
J. G. Seidman ◽  
Christine E. Seidman
Keyword(s):  
Rna Interference ◽  
Hypertrophic Cardiomyopathy ◽  
Clinical Phenotype ◽  
Therapeutic Benefit ◽  
Myosin Heavy Chains ◽  
Specific Expression ◽  
Adeno Associated Virus ◽  
Heavy Chains ◽  
Allele Specific ◽  
Sarcomere Proteins

Dominant mutations in sarcomere proteins such as the myosin heavy chains (MHC) are the leading genetic causes of human hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy. We found that expression of the HCM-causing cardiac MHC gene (Myh6) R403Q mutation in mice can be selectively silenced by an RNA interference (RNAi) cassette delivered by an adeno-associated virus vector. RNAi-transduced MHC403/+mice developed neither hypertrophy nor myocardial fibrosis, the pathologic manifestations of HCM, for at least 6 months. Because inhibition of HCM was achieved by only a 25% reduction in the levels of the mutant transcripts, we suggest that the variable clinical phenotype in HCM patients reflects allele-specific expression and that partial silencing of mutant transcripts may have therapeutic benefit.

scholarly journals Impeding transcription of expanded microsatellite repeats by deactivated Cas9

2017 ◽  
Author(s):  
Belinda S. Pinto ◽  
Tanvi Saxena ◽  
Ruan Oliveira ◽  
Héctor R. Méndez-Gómez ◽  
John D. Cleary ◽  
...  
Keyword(s):  
Corneal Dystrophy ◽  
Therapeutic Benefit ◽  
Systemic Delivery ◽  
Microsatellite Repeat ◽  
Aberrant Splicing ◽  
Adeno Associated Virus ◽  
Microsatellite Repeats ◽  
Repeat Sequences ◽  
Rna Foci ◽  
Splicing Patterns

SummaryTranscription of expanded microsatellite repeats is associated with multiple human diseases, including myotonic dystrophy, Fuchs’ endothelial corneal dystrophy, andC9orf72-ALS/FTD. Eliminating or reducing production of RNA and proteins arising from these expanded loci holds therapeutic benefit. Here, we tested the hypothesis that a deactivated form of the Cas9 enzyme impedes transcription across expanded microsatellites. We observed a repeat length-, PAM-, and strand-dependent reduction in the abundance of repeat-containing RNAs upon targeting dCas9 directly to repeat sequences. Aberrant splicing patterns were rescued in DM1 cells, and production of RAN peptides characteristic of DM1, DM2, andC9orf72-ALS/FTD cells was drastically decreased. Systemic delivery of dCas9/gRNA by adeno-associated virus led to reductions in pathological RNA foci, rescue of chloride channel 1 protein expression, and decreased myotonia. These observations suggest that transcription of microsatellite repeat-containing RNAs is more sensitive to perturbation than transcription of other RNAs, indicating potentially viable strategies for therapeutic intervention.

scholarly journals Adeno-associated virus–targeted disruption of the CFTR gene in cloned ferrets

2008 ◽  
Vol 118 (4) ◽  
pp. 1578-1583 ◽  
Author(s):  
Xingshen Sun ◽  
Ziying Yan ◽  
Yaling Yi ◽  
Ziyi Li ◽  
Diana Lei ◽  
...  
Keyword(s):  
Cftr Gene ◽  
Targeted Disruption ◽  
Adeno Associated Virus

Immune Electron Microscopy (IEM) of a Canine Adeno-Associated Virus

1974 ◽  
Vol 32 ◽  
pp. 256-257
Author(s):  
Gunter F. Thomas ◽  
M. David Hoggan
Keyword(s):  
Electron Microscopy ◽  
Cell Cultures ◽  
Complement Fixation ◽  
Hepatitis Virus ◽  
Wide Distribution ◽  
Immune Electron Microscopy ◽  
Adeno Associated Virus ◽  
Virus Like Particle ◽  
Dog Kidney ◽  
Green Monkeys

In 1968, Sugimura and Yanagawa described a small 25 nm virus like particle in association with the Matsuda strain of infectious canine hepatitis virus (ICHV). Domoto and Yanagawa showed that this particle was dependent on ICHV for its replication in primary dog kidney cell cultures (PDK) and was resistant to heating at 70°C for 10 min, and concluded that it was a canine adeno-associated virus (CAAV). Later studies by Onuma and Yanagawa compared CAAV with the known human serotypes (AAV 1, 2, 3) and AAV-4, known to be associated with African Green Monkeys. Using the complement fixation (CF) test, they found that CAAV was serologically related to AAV-3 and had wide distribution in the dog population of Japan.

1509: Adeno-Associated Virus-Mediated Human IL-10 Gene Transfer Suppresses the Development of Experimental Autoimmune Orchitis

2005 ◽  
Vol 173 (4S) ◽  
pp. 409-409
Author(s):  
Masami Watanabe ◽  
Atsushi Nagai ◽  
Norihiro Kusumi ◽  
Yasutomo Nasu ◽  
Hiromi Kumon ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Adeno Associated Virus ◽  
Autoimmune Orchitis ◽  
Experimental Autoimmune

1011: Suppression of Renal Cell Carcinoma Lung Metastasis by Adeno-Associated Virus (AAV) Mediated Gene Transfer of a Soluble Receptor of VEGF

2004 ◽  
Vol 171 (4S) ◽  
pp. 267-267
Author(s):  
Ichiro Yoshimura ◽  
Yasunori Mizuguchi ◽  
Akira Miyajima ◽  
Tomohiko Asano ◽  
Hiroaki Mizukami ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Gene Transfer ◽  
Cell Carcinoma ◽  
Lung Metastasis ◽  
Renal Cell ◽  
Soluble Receptor ◽  
Adeno Associated Virus
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