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Adeno associated

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https://www.readbyqxmd.com/read/29453976/cell-type-specific-expression-of-constitutively-active-rheb-promotes-regeneration-of-bulbospinal-respiratory-axons-following-cervical-sci
#1
Mark W Urban, Biswarup Ghosh, Laura R Strojny, Cole G Block, Sara M Blazejewski, Megan C Wright, George M Smith, Angelo C Lepore
Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential...
February 14, 2018: Experimental Neurology
https://www.readbyqxmd.com/read/29453308/sex-specific-mechanisms-of-resistance-vessel-endothelial-dysfunction-induced-by-cardiometabolic-risk-factors
#2
Ana P Davel, Qing Lu, M Elizabeth Moss, Sitara Rao, Imran J Anwar, Jennifer J DuPont, Iris Z Jaffe
BACKGROUND: The incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular outcomes, but the molecular mechanisms are unclear. Because obesity is associated with mineralocorticoid receptor (MR) activation, we tested the hypothesis that MR in endothelial cells contribute to sex differences in resistance vessel dysfunction in response to cardiometabolic risk factors. METHODS AND RESULTS: Male and female endothelial cell-specific MR knockout mice and MR-intact littermates were randomized to high-fat-diet-induced obesity or obesity with hyperlipidemia induced by adeno-associated virus-based vector targeting transfer of the mutant stable form (DY mutation) of the human PCSK9 (proprotein convertase subtilisin/kexin type 9) gene and compared with control diet...
February 16, 2018: Journal of the American Heart Association
https://www.readbyqxmd.com/read/29449536/impaired-autophagic-flux-is-associated-with-the-severity-of-trauma-and-the-role-of-a-2a-r-in-brain-cells-after-traumatic-brain-injury
#3
Xu-Jia Zeng, Ping Li, Ya-Lei Ning, Yan Zhao, Yan Peng, Nan Yang, Zi-Ai Zhao, Jiang-Fan Chen, Yuan-Guo Zhou
Recent studies have shown that after traumatic brain injury (TBI), the number of autophagosomes is markedly increased in brain cells surrounding the wound; however, whether autophagy is enhanced or suppressed by TBI remains controversial. In our study, we used a controlled cortical impact system to establish models of mild, moderate and severe TBI. In the mild TBI model, the levels of autophagy-related protein 6 (Beclin1) and autophagy-related protein 12 (ATG12)-autophagy-related protein 5 (ATG5) conjugates were increased, indicating the enhanced initiation of autophagy...
February 14, 2018: Cell Death & Disease
https://www.readbyqxmd.com/read/29448836/aav8-gene-therapy-rescues-the-newborn-phenotype-of-a-mouse-model-of-crigler-najjar
#4
Jenny A Greig, Jayme M L Nordin, Christine Draper, Peter Bell, James M Wilson
Adeno-associated viral (AAV) vectors can target the liver, making them an attractive platform for gene therapy approaches that require the correction of hepatocytes. Crigler-Najjar syndrome is an autosomal recessive disorder of bilirubin metabolism that occurs when the liver's uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1) enzyme activity is partially or completely absent. This syndrome is characterized by elevated bilirubin levels in the blood. We developed an AAV8 vector expressing a codon-optimized human version of UGT1A1 from a liver-specific promoter...
February 16, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29447858/intrathecal-injection-of-scaav9-higf1-prolongs-the-survival-of-als-model-mice-by-inhibiting-the-nf-kb-pathway
#5
HaoJie Hu, HuiQian Lin, WeiSong Duan, Can Cui, ZhongYao Li, YaKun Liu, Wan Wang, Di Wen, Ying Wang, ChunYan Li
Amyotrophic lateral sclerosis (ALS) is a chronic, fatal neurodegenerative disorder characterized by the progressive loss of upper and lower motor neurons. Currently, there is no effective drug for ALS. Recent studies in ALS model mice have shown that insulin-like growth factor-1 (IGF1) may be a promising therapeutic drug. We demonstrate that self-complementary adeno-associated virus serum type 9 encoding the human IGF1 (scAAV9-hIGF1) could significantly postpone the onset and slow down the progression of the disease owning to inhibiting the NF-κB signalling pathway...
February 12, 2018: Neuroscience
https://www.readbyqxmd.com/read/29446741/whats%C3%A2-new-in-gene-therapy-of-hemophilia
#6
E Carlos Rodriguez-Merchan
BACKGROUND: Several methods have been investigated to effectively and safely transmit genes that stimulate cells to release therapeutic factor VIII (FVIII) and factor IX (FIX) into the circulation of people with hemophilia (PWH). OBJECTIVE: To review the role of gene therapy (GT) in PWH. METHODS: A Cochrane Library and PubMed (MEDLINE) search related to the role of GT in hemophilia was analyzed. RESULTS: The most promising vectors for hemophilia GT are adeno-associated virus (AAV) and lentivirus...
February 14, 2018: Current Gene Therapy
https://www.readbyqxmd.com/read/29439717/dysregulated-phosphorylation-of-rab-gtpases-by-lrrk2-induces-neurodegeneration
#7
Ga Ram Jeong, Eun-Hae Jang, Jae Ryul Bae, Soyoung Jun, Ho Chul Kang, Chi-Hu Park, Joo-Ho Shin, Yukio Yamamoto, Keiko Tanaka-Yamamoto, Valina L Dawson, Ted M Dawson, Eun-Mi Hur, Byoung Dae Lee
BACKGROUND: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial and sporadic Parkinson's disease (PD). Elevated kinase activity is associated with LRRK2 toxicity, but the substrates that mediate neurodegeneration remain poorly defined. Given the increasing evidence suggesting a role of LRRK2 in membrane and vesicle trafficking, here we systemically screened Rab GTPases, core regulators of vesicular dynamics, as potential substrates of LRRK2 and investigated the functional consequence of such phosphorylation in cells and in vivo...
February 13, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29435804/human-neural-stem-cells-with-gdnf-site-specific-integration-at-aavs1-by-using-aav-vectors-retained-their-stemness
#8
Jinju Zhang, Xiaomei Liu, Yun Zhang, Zuo Luan, Yinxiang Yang, Zhaoyan Wang, Chun Zhang
The neural stem cells (NSCs) have the ability to self-renew, and to migrate to pathologically altered regions of the central nervous system. Glial cell derived neurotrophic factor (GDNF) could protect dopamine neurons and rescue motor neurons in vivo, which has been proposed as a promising candidate for the treatments of degenerative neurological diseases. In order to combine the advantages of neurotrophic factors and stem cells in clinical therapy, we established the modified hNSCs that has site-specific integration of GDNF gene by using recombinant adeno-associated virus (rAAV) vectors...
February 12, 2018: Neurochemical Research
https://www.readbyqxmd.com/read/29435047/gtsf1-gene-may-serve-as-a-novel-potential-diagnostic-biomarker-for-liver-cancer
#9
De-Yong Gao, Yun Ling, Xiao-Li Lou, Ying-Ying Wang, Liang-Ming Liu
The gametocyte-specific factor 1 (GTSF1) gene participates in DNA methylation and retrotransposon activation in germ cells, particularly during cell proliferation. The present study aimed to assess the level of GTSF1 gene expression in liver cancer tumor tissues, and its role in human hepatoma cell lines in vitro and in a nude mouse model in vivo. GTSF1 gene expression was detected in liver cancer tumor tissues, compared with in healthy controls, via reverse transcription quantitative polymerase chain reaction...
March 2018: Oncology Letters
https://www.readbyqxmd.com/read/29434771/adeno-associated-virus-serotype-9-mediated-vascular-endothelial-growth-factor-gene-overexpression-in-mdx-mice
#10
Xueqin Song, Ya Zhang, Zhigang Hou, Hongran Wu, Shan Lu, Jin Tang, Xuexiao Chen, Hongying Cui, Yuan Li, Yue Bi, Weisong Duan, Zhongyao Li, Chunyan Li
Duchenne muscular dystrophy (DMD) is a fatal neuromuscular disease caused by the absence of dystrophin. Vascular endothelial growth factor (VEGF) is a heparin-binding dimeric glycoprotein and principal angiogenic factor stimulating the migration, proliferation and expression of various genes in endothelial cells. Recently, VEGF was demonstrated to exhibit an antiapoptotic and direct myogenic effect, as well as to enhance muscle force restoration subsequent to traumatic injury. Therefore, the present study attempted to assess the muscle damage of VEGF overexpression in mdx mice...
February 2018: Experimental and Therapeutic Medicine
https://www.readbyqxmd.com/read/29434670/advances-in-spinal-muscular-atrophy-therapeutics
#11
REVIEW
Valeria Parente, Stefania Corti
Spinal muscular atrophy (SMA) is a progressive, recessively inherited neuromuscular disease, characterized by the degeneration of lower motor neurons in the spinal cord and brainstem, which leads to weakness and muscle atrophy. SMA currently represents the most common genetic cause of infant death. SMA is caused by the lack of survival motor neuron (SMN) protein due to mutations, which are often deletions, in the SMN1 gene. In the absence of treatments able to modify the disease course, a considerable burden falls on patients and their families...
2018: Therapeutic Advances in Neurological Disorders
https://www.readbyqxmd.com/read/29433982/bimolecular-fluorescence-complementation-of-alpha-synuclein-demonstrates-its-oligomerization-with-dopaminergic-phenotype-in-mice
#12
Waijiao Cai, Danielle Feng, Michael A Schwarzschild, Pamela J McLean, Xiqun Chen
Alpha-synuclein (αSyn) is encoded by the first causal gene identified in Parkinson's disease (PD) and is the main component of Lewy bodies, a pathological hallmark of PD. aSyn-based animal models have contributed to our understanding of PD pathophysiology and to the development of therapeutics. Overexpression of human wildtype αSyn by viral vectors in rodents recapitulates the loss of dopaminergic neurons from the substantia nigra, another defining pathological feature of the disease. The development of a rat model exhibiting bimolecular fluorescence complementation (BiFC) of αSyn by recombinant adeno-associated virus facilitates detection of the toxic αSyn oligomers species...
January 31, 2018: EBioMedicine
https://www.readbyqxmd.com/read/29433937/long-term-improvement-of-neurological-signs-and-metabolic-dysfunction-in-a-mouse-model-of-krabbe-s-disease-after-global-gene-therapy
#13
Michael S Marshall, Yazan Issa, Benas Jakubauskas, Monika Stoskute, Vince Elackattu, Jeffrey N Marshall, Wil Bogue, Duc Nguyen, Zane Hauck, Emily Rue, Subha Karumuthil-Melethil, Violeta Zaric, Maarten Bosland, Richard B van Breemen, Maria I Givogri, Steven J Gray, Stephen J Crocker, Ernesto R Bongarzone
We report a global adeno-associated virus (AAV)9-based gene therapy protocol to deliver therapeutic galactosylceramidase (GALC), a lysosomal enzyme that is deficient in Krabbe's disease. When globally administered via intrathecal, intracranial, and intravenous injections to newborn mice affected with GALC deficiency (twitcher mice), this approach largely surpassed prior published benchmarks of survival and metabolic correction, showing long-term protection of demyelination, neuroinflammation, and motor function...
January 17, 2018: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/29433343/cardiac-specific-expression-of-%C3%A2-h2-r15-mini-dystrophin-normalized-all-ecg-abnormalities-and-the-end-diastolic-volume-in-a-23-m-old-mouse-model-of-duchenne-dilated-cardiomyopathy
#14
Nalinda B Wasala, Jin-Hong Shin, Yi Lai, Yongping Yue, Federica Montanaro, Dongsheng Duan
Heart disease is a major health threat for Duchenne/Becker muscular dystrophy patients and carriers. Expression of a 6 to 8-kb mini-dystrophin gene in the heart holds promise to dramatically change the disease course. However the mini-dystrophin gene cannot be easily studied with adeno-associated virus (AAV) gene delivery because the size of the minigene exceeds AAV packaging capacity. We previously studied cardiac protection of the ∆H2-R19 minigene using the cardiac specific transgenic approach. Although this minigene fully normalized skeletal muscle force, it only partially corrected ECG and heart hemodynamics in dystrophin-null mdx mice that had moderate cardiomyopathy...
February 13, 2018: Human Gene Therapy
https://www.readbyqxmd.com/read/29427611/imaging-pathological-activities-of-human-brain-tissue-in-organotypic-culture
#15
Caroline Le Duigou, Etienne Savary, Mélanie Morin-Brureau, Daniel Gomez-Dominguez, André Sobczyk, Farah Chali, Giampaolo Milior, Larissa Kraus, Jochen C Meier, Dimitri M Kullmann, Bertrand Mathon, Liset Menendez de la Prida, Georg Dorfmuller, Johan Pallud, Emmanuel Eugène, Stéphane Clemenceau, Richard Miles
BACKGROUND: Insights into human brain diseases may emerge from tissue obtained after operations on patients. However techniques requiring transduction of transgenes carried by viral vectors cannot be applied to acute human tissue. NEW METHOD: We show that organotypic culture techniques can be used to maintain tissue from patients with three different neurological syndromes for several weeks in vitro. Optimized viral vector techniques and promoters for transgene expression are described...
February 7, 2018: Journal of Neuroscience Methods
https://www.readbyqxmd.com/read/29422542/protection-of-nigral-dopaminergic-neurons-by-aav1-transduction-with-rheb-s16h-against-neurotoxic-inflammation-in-vivo
#16
Sehwan Kim, Gyeong Joon Moon, Yong-Seok Oh, Jungha Park, Won-Ho Shin, Jae Yeong Jeong, Kwang Shik Choi, Byung Kwan Jin, Nikolai Kholodilov, Robert E Burke, Hyung-Jun Kim, Chang Man Ha, Seok-Geun Lee, Sang Ryong Kim
We recently reported that adeno-associated virus serotype 1 (AAV1) transduction of murine nigral dopaminergic (DA) neurons with constitutively active ras homolog enriched in brain with a mutation of serine to histidine at position 16 [Rheb(S16H)] induced the production of neurotrophic factors, resulting in neuroprotective effects on the nigrostriatal DA system in animal models of Parkinson's disease (PD). To further investigate whether AAV1-Rheb(S16H) transduction has neuroprotective potential against neurotoxic inflammation, which is known to be a potential event related to PD pathogenesis, we examined the effects of Rheb(S16H) expression in nigral DA neurons under a neurotoxic inflammatory environment induced by the endogenous microglial activator prothrombin kringle-2 (pKr-2)...
February 9, 2018: Experimental & Molecular Medicine
https://www.readbyqxmd.com/read/29414605/use-of-induced-pluripotent-stem-cell-models-to-probe-the-pathogenesis-of-choroideremia-and-to-develop-a-potential-treatment
#17
Thu T Duong, Vidyullatha Vasireddy, Pavitra Ramachandran, Pamela S Herrera, Lanfranco Leo, Carrie Merkel, Jean Bennett, Jason A Mills
Choroideremia (CHM) is a rare monogenic, X-linked recessive inherited retinal degeneration resulting from mutations in the Rab Escort Protein-1 (REP1) encoding CHM gene. The primary retinal cell type leading to CHM is unknown. In this study, we explored the utility of induced pluripotent stem cell-derived models of retinal pigmented epithelium (iPSC-RPE) to study disease pathogenesis and a potential gene-based intervention in four different genetically distinct forms of CHM. A number of abnormal cell biologic, biochemical, and physiologic functions were identified in the CHM mutant cells...
January 27, 2018: Stem Cell Research
https://www.readbyqxmd.com/read/29414380/gene-therapy-mediated-seizure-suppression-in-genetic-generalised-epilepsy-neuropeptide-y-overexpression-in-a-rat-model
#18
Kim L Powell, Xavier Fitzgerald, Claire Shallue, Valentina Jovanovska, Matthias Klugmann, Georg Von Jonquieres, Terence J O'Brien, Margaret J Morris
Neuropeptide Y (NPY) is an important 36 amino acid peptide that is abundantly expressed in the mammalian CNS and is known to be an endogenous modulator of seizure activity, including in rat models of Genetic Generalised Epilepsy (GGE) with absence seizures. Studies have shown that viral-mediated "gene therapy" with overexpression of NPY in the hippocampus can suppress seizures in acquired epilepsy animal models. This study investigated whether NPY gene delivery to the thalamus or somatosensory cortex, using recombinant adeno-associated viral vector (rAAV), could produce sustained seizure suppression in the GAERS model of GGE with absence seizures...
January 29, 2018: Neurobiology of Disease
https://www.readbyqxmd.com/read/29410463/opa1-gene-therapy-prevents-retinal-ganglion-cell-loss-in-a-dominant-optic-atrophy-mouse-model
#19
Emmanuelle Sarzi, Marie Seveno, Camille Piro-Mégy, Lucie Elzière, Mélanie Quilès, Marie Péquignot, Agnès Müller, Christian P Hamel, Guy Lenaers, Cécile Delettre
Dominant optic atrophy (DOA) is a rare progressive and irreversible blinding disease which is one of the most frequent forms of hereditary optic neuropathy. DOA is mainly caused by dominant mutation in the OPA1 gene encoding a large mitochondrial GTPase with crucial roles in membrane dynamics and cell survival. Hereditary optic neuropathies are commonly characterized by the degeneration of retinal ganglion cells, leading to the optic nerve atrophy and the progressive loss of visual acuity. Up to now, despite increasing advances in the understanding of the pathological mechanisms, DOA remains intractable...
February 6, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29409011/cardiomyocyte-specific-deletion-of-sirt1-gene-sensitizes-myocardium-to-ischemia-and-reperfusion-injury
#20
Lin Wang, Nanhu Quan, Wanqing Sun, Xu Chen, Courtney Cates, Thomas Rousselle, Xinchun Zhou, Xuezhong Zhao, Ji Li
Aim: A longevity gene, Sirtuin 1 (SIRT1) and energy sensor AMP-activated protein kinase (AMPK) have common activators such as caloric restriction, oxidative stress and exercise. The objective of this study is to characterize the role of cardiomyocyte SIRT1 in age-related impaired ischemic AMPK activation and increased susceptibility to ischemic insults. Methods and Results: Mice were subjected to ligation of left anterior descending coronary artery for in vivo ischemic models...
February 2, 2018: Cardiovascular Research
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