scholarly journals 721. Lentiviral Mediated Neonatal Gene Therapy for Krabbe Disease Model Mouse

2011 ◽  
Vol 19 ◽  
pp. S275
Bioimpacts ◽  
2021 ◽  
Vol 11 (2) ◽  
pp. 135-146
Author(s):  
Mohammad A Rafi ◽  
Paola Luzi ◽  
David A Wenger

Introduction: Krabbe disease (KD) is an autosomal recessive disorder caused by mutations in the galactocerebrosidase (GALC) gene resulting in neuro-inflammation and defective myelination in the central and peripheral nervous systems. Most infantile patients present with clinical features before six months of age and die before two years of age. The only treatment available for pre-symptomatic or mildly affected individuals is hematopoietic stem cell transplantation (HSCT). In the animal models, combining bone marrow transplantation (BMT) with gene therapy has shown the best results in disease outcome. In this study, we examine the outcome of gene therapy alone. Methods: Twitcher (twi) mice used in the study, have a W339X mutation in the GALC gene. Genotype identification of the mice was performed shortly after birth or post-natal day 1 (PND1), using polymerase chain reaction on the toe clips followed by restriction enzyme digestion and electrophoresis. Eight or nine-day-old affected mice were used for gene therapy treatment alone or combined with BMT. While iv injection of 4 × 1013 gc/kg of body weight of viral vector was used originally, different viral titers were also used without BMT to evaluate their outcomes. Results: When the standard viral dose was increased four- and ten-fold (4X and 10X) without BMT, the lifespans were increased significantly. Without BMT the affected mice were fertile, had the same weight and appearance as wild type mice and had normal strength and gait. The brains showed no staining for CD68, a marker for activated microglia/macrophages, and less astrogliosis than untreated twi mice. Conclusion: Our results demonstrate that, it may be possible to treat human KD patients with high dose AAVrh10 without blood stem cell transplantation which would eliminate the side effects of HSCT.


Bioimpacts ◽  
2016 ◽  
Vol 6 (2) ◽  
pp. 69-70 ◽  
Author(s):  
Mohammad A. Rafi

2006 ◽  
Vol 14 (7S_Part_5) ◽  
pp. P305-P305
Author(s):  
Yodai Kobayashi ◽  
Kousuke Shimada ◽  
Eri Mitsuyama ◽  
Tetsuya Kuhara ◽  
Akihito Yasuoka ◽  
...  

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
S. M. Shamsul Islam ◽  
Hae-Ok Byun ◽  
Bunsoon Choi ◽  
Seonghyang Sohn

Behçet’s disease (BD) is an autoinflammatory disease that can lead to life- and sight-threating complications. Dendritic cells (DCs) are the most potent antigen-presenting cells that can regulate multiple inflammatory pathways. The objective of this study was to investigate the association of the DC stimulatory molecule CD83 with BD. Frequencies of costimulatory molecules expressing DCs in peripheral blood leukocytes (PBL) were measured by flow cytometry (FACS). The severity of symptoms in HSV-1-induced BD symptomatic mice was also assessed. Frequencies of CD83-positive cells were significantly increased in mice exhibiting BD symptoms, compared to those in asymptomatic mice. Abatacept, a CD80/86 blocker, significantly decreased the frequencies of CD83-positive cells in a time- and dose-dependent manner. BD symptomatic mice treated with Abatacept showed gradual reduction in the severity score of symptoms. Intraperitoneal injection of CD83 siRNA significantly reduced the frequencies of CD83-positive cells in PBL and peritoneal macrophages. After CD83 siRNA injection, BD symptoms of mice were improved and disease severity was decreased. Discontinuation of CD83 siRNA deteriorated symptoms while readministration of CD83 siRNA again improved BD symptoms of mice. These results clearly indicate the involvement of CD83-expressing cells in the inflammatory symptoms of BD. Therefore, CD83 might be useful as a therapeutic target for BD.


2006 ◽  
Vol 350 (3) ◽  
pp. 530-536 ◽  
Author(s):  
Yoichiro Nishida ◽  
Takanori Yokota ◽  
Tsubura Takahashi ◽  
Toshiki Uchihara ◽  
Kou-ichi Jishage ◽  
...  

PLoS ONE ◽  
2017 ◽  
Vol 12 (6) ◽  
pp. e0178978 ◽  
Author(s):  
Yasuhiro Ogawa ◽  
Katsutoshi Kaizu ◽  
Yusuke Yanagi ◽  
Subaru Takada ◽  
Hitoshi Sakuraba ◽  
...  

2010 ◽  
Vol 20 (01n02) ◽  
pp. 45-50 ◽  
Author(s):  
K. FUJIKI ◽  
S. MATSUYAMA ◽  
K. ISHII ◽  
H. YAMAZAKI ◽  
A. TERAKAWA ◽  
...  

In a biological body, trace elements including metallic elements play important roles. Knowing their spatial distribution and amounts, we can find out some relations among a physiological role of the trace element in vivo, the function, and the disease appearance. In this study, we investigated a method to obtain elemental distributions in whole brain slice taken from mental disease model mice and control mice using in-air submilli-PIXE camera at Tohoku University. We administered 5-BrdU that was the analogue of the thymidine as a marker to detect a new born cell in especially the dentate gyrus of the hippocampus. We obtained the elemental distributions of the whole brain of subject and control mice. From elemental distributions of the brain of a mental disease model mouse, a brain contained light elements, such as P , S , Cl and K , which were uniformly distributed over the brain. Fe was accumulated in the specific area of brain. Elemental concentration of Fe was more than 10 times higher than that in the other. However, the accumulation of iron in brain slices was not observed in those of control mice. Zn is accumulated in the vicinity in hippocampus. Br was uniformly distributed over the brain. The submilli-PIXE camera will provide a powerful tool for this research.


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