scholarly journals Adenoassociated Virus Serotype 9-Mediated Gene Therapy for X-Linked Adrenoleukodystrophy

2015 ◽  
Vol 23 (5) ◽  
pp. 824-834 ◽  
Author(s):  
Yi Gong ◽  
Dakai Mu ◽  
Shilpa Prabhakar ◽  
Ann Moser ◽  
Patricia Musolino ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Virus Serotype ◽  
Adenoassociated Virus

scholarly journals Safety profile of the transcription factor EB (TFEB)-based gene therapy through intracranial injection in mice

2020 ◽  
Vol 11 (1) ◽  
pp. 241-250
Author(s):  
Zhenyu Li ◽  
Guangqian Ding ◽  
Yudi Wang ◽  
Zelong Zheng ◽  
Jianping Lv
Keyword(s):  
Gene Therapy ◽  
Transcription Factor ◽  
Neurodegenerative Diseases ◽  
Brain Tissue ◽  
Inflammatory Responses ◽  
Tissue Samples ◽  
Protein Levels ◽  
Virus Serotype ◽  
Transcription Factor Eb ◽  
The Brain

AbstractTranscription factor EB (TFEB)-based gene therapy is a promising therapeutic strategy in treating neurodegenerative diseases by promoting autophagy/lysosome-mediated degradation and clearance of misfolded proteins that contribute to the pathogenesis of these diseases. However, recent findings have shown that TFEB has proinflammatory properties, raising the safety concerns about its clinical application. To investigate whether TFEB induces significant inflammatory responses in the brain, male C57BL/6 mice were injected with phosphate-buffered saline (PBS), adeno-associated virus serotype 8 (AAV8) vectors overexpressing mouse TFEB (pAAV8-CMV-mTFEB), or AAV8 vectors expressing green fluorescent proteins (GFPs) in the barrel cortex. The brain tissue samples were collected at 2 months after injection. Western blotting and immunofluorescence staining showed that mTFEB protein levels were significantly increased in the brain tissue samples of mice injected with mTFEB-overexpressing vectors compared with those injected with PBS or GFP-overexpressing vectors. pAAV8-CMV-mTFEB injection resulted in significant elevations in the mRNA and protein levels of lysosomal biogenesis indicators in the brain tissue samples. No significant changes were observed in the expressions of GFAP, Iba1, and proinflammation mediators in the pAAV8-CMV-mTFEB-injected brain compared with those in the control groups. Collectively, our results suggest that AAV8 successfully mediates mTFEB overexpression in the mouse brain without inducing apparent local inflammation, supporting the safety of TFEB-based gene therapy in treating neurodegenerative diseases.

Abstract 339: Long-term AAV6-βARKct Myocardial Gene Therapy Improves Cardiac Function Via Restoration Of β-Adrenergic Receptor Signaling And Neurohormonal Status Of The Failing Heart

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Giuseppe Rengo ◽  
Anastasios Lymperopoulos ◽  
Carmela Zincarelli ◽  
Maria Donniacuo ◽  
Stephen Soltys ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Delivery ◽  
Cardiac Function ◽  
Adrenergic Receptor ◽  
Fluorescent Protein ◽  
Heart Function ◽  
Weight Ratio ◽  
Intramyocardial Injection ◽  
Molecular Abnormalities ◽  
Virus Serotype

BACKGROUND: The up-regulation of G protein-coupled receptor kinase-2 (GRK2) that is present in compromised myocardium contributes to dysfunctional β-adrenergic receptor (βAR) signaling and cardiac function in heart failure (HF). The peptide βARKct, which inhibits the activation of GRK2, has been shown in acute gene transfer experiments to rescue HF. This study was designed to evaluate chronic βARKct expression in post-myocardial infarction (MI) induced HF using stable myocardial gene delivery with adeno-associated virus serotype-6 (AAV6). METHODS AND RESULTS: In 12 week post-MI HF rats, we delivered βARKct or as a control, Green Fluorescent Protein, via direct intramyocardial injection. We also treated groups with concurrent administration of metoprolol. We found robust and long-lasting (up to 12 weeks post-delivery) transgene expression in the left ventricle (LV) and βARKct expression resulted in significantly improved global heart function as LV ejection fraction and ±dP/dt were increased, whereas LV end diastolic diameter and pressure were decreased. At the molecular level, cardiac βAR density and cAMP accumulation significantly improved over control groups. Fibrotic and hypertrophy markers, as well as heart-to-body weight ratio were markedly decreased by βARKct gene therapy indicating active reversal of adverse LV remodeling. For the first time, we found that chronic βARKct expression and normalization of cardiac βAR signaling led to a reduction of circulating levels of cardiotoxic neurohormones (catecholamines and aldosterone) demonstrating a potential additive mechanism of GRK2 inhibition. Concomitant metoprolol administration preserved the gain in inotropy achieved by βARKct, suggesting compatibility of these two therapeutic modalities, however, metoprolol alone only prevented the deterioration of cardiac function in HF. CONCLUSIONS : Chronic cardiac βARKct gene therapy for HF treatment via AAV6-mediated intracardiac gene delivery is feasible and results in improved cardiac function accompanied by restoration of βAR molecular abnormalities and amelioration of neurohormonal status of HF. These findings suggest βARKct gene therapy might be clinically applicable and of significant value for human HF treatment. This research has received full or partial funding support from the American Heart Association, AHA Great Rivers Affiliate (Delaware, Kentucky, Ohio, Pennsylvania & West Virginia).

scholarly journals Complete Correction of Brain and Spinal Cord Pathology in Metachromatic Leukodystrophy Mice

2021 ◽  
Vol 14 ◽  
Author(s):  
Emilie Audouard ◽  
Valentin Oger ◽  
Béatrix Meha ◽  
Nathalie Cartier ◽  
Caroline Sevin ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Metachromatic Leukodystrophy ◽  
Early Death ◽  
Lysosomal Storage ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Brain And Spinal Cord ◽  
Sulfatide Accumulation

Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder characterized by accumulation of sulfatides in both glial cells and neurons. MLD results from an inherited deficiency of arylsulfatase A (ARSA) and myelin degeneration in the central and peripheral nervous systems. Currently, no effective treatment is available for the most frequent late infantile (LI) form of MLD after symptom onset. The LI form results in rapid neurological degradation and early death. ARSA enzyme must be rapidly and efficiently delivered to brain and spinal cord oligodendrocytes of patients with LI MLD in order to potentially stop the progression of the disease. We previously showed that brain gene therapy with adeno-associated virus serotype rh10 (AAVrh10) driving the expression of human ARSA cDNA alleviated most long-term disease manifestations in MLD mice but was not sufficient in MLD patient to improve disease progression. Herein, we evaluated the short-term effects of intravenous AAVPHP.eB delivery driving the expression of human ARSA cDNA under the control of the cytomegalovirus/b-actin hybrid (CAG) promoter in 6-month-old MLD mice that already show marked sulfatide accumulation and brain pathology. Within 3 months, a single intravenous injection of AAVPHP.eB-hARSA-HA resulted in correction of brain and spinal cord sulfatide storage, and improvement of astrogliosis and microgliosis in brain and spinal cord of treated animals. These results strongly support to consider the use of AAVPHP.eB-hARSA vector for intravenous gene therapy in symptomatic rapidly progressing forms of MLD.

scholarly journals The 37/67-Kilodalton Laminin Receptor Is a Receptor for Adeno-Associated Virus Serotypes 8, 2, 3, and 9

2006 ◽  
Vol 80 (19) ◽  
pp. 9831-9836 ◽  
Author(s):  
Bassel Akache ◽  
Dirk Grimm ◽  
Kusum Pandey ◽  
Stephen R. Yant ◽  
Hui Xu ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cultured Cells ◽  
Human Gene ◽  
Laminin Receptor ◽  
Transduction Efficiency ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Tumor Gene

ABSTRACT Adeno-associated virus serotype 8 (AAV8) is currently emerging as a powerful gene transfer vector, owing to its capability to efficiently transduce many different tissues in vivo. While this is believed to be in part due to its ability to uncoat more readily than other AAV serotypes such as AAV2, understanding all the processes behind AAV8 transduction is important for its application and optimal use in human gene therapy. Here, we provide the first report of a cellular receptor for AAV8, the 37/67-kDa laminin receptor (LamR). We document binding of LamR to AAV8 capsid proteins and intact virions in vitro and demonstrate its contribution to AAV8 transduction of cultured cells and mouse liver in vivo. We also show that LamR plays a role in transduction by three other closely related serotypes (AAV2, -3, and -9). Sequence and deletion analysis allowed us to map LamR binding to two protein subdomains predicted to be exposed on the AAV capsid exterior. Use of LamR, which is constitutively expressed in many clinically relevant tissues and is overexpressed in numerous cancers, provides a molecular explanation for AAV8's broad tissue tropism. Along with its robust transduction efficiency, our findings support the continued development of AAV8-based vectors for clinical applications in humans, especially for tumor gene therapy.

scholarly journals Data-driven evolution of neurosurgical gene therapy delivery in Parkinson’s disease

2020 ◽  
Vol 91 (11) ◽  
pp. 1210-1218 ◽  
Author(s):  
R Mark Richardson ◽  
Krystof S Bankiewicz ◽  
Chadwick W Christine ◽  
Amber D Van Laar ◽  
Robert E Gross ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Gene Therapy ◽  
Parkinson's Disease ◽  
Viral Vector ◽  
Data Driven ◽  
Surgical Approaches ◽  
Acid Decarboxylase ◽  
Projection Neurons ◽  
Virus Serotype ◽  
Vector Delivery

Loss of nigrostriatal dopaminergic projection neurons is a key pathology in Parkinson’s disease, leading to abnormal function of basal ganglia motor circuits and the accompanying characteristic motor features. A number of intraparenchymally delivered gene therapies designed to modify underlying disease and/or improve clinical symptoms have shown promise in preclinical studies and subsequently were evaluated in clinical trials. Here we review the challenges with surgical delivery of gene therapy vectors that limited therapeutic outcomes in these trials, particularly the lack of real-time monitoring of vector administration. These challenges have recently been addressed during the evolution of novel techniques for vector delivery that include the use of intraoperative MRI. The preclinical development of these techniques are described in relation to recent clinical translation in an adeno-associated virus serotype 2-mediated human aromatic L-amino acid decarboxylase gene therapy development programme. This new paradigm allows visualisation of the accuracy and adequacy of viral vector delivery within target structures, enabling intertrial modifications in surgical approaches, cannula design, vector volumes and dosing. The rapid, data-driven evolution of these procedures is unique and has led to improved vector delivery.

scholarly journals Modulation of the liver immune microenvironment by the adeno-associated virus serotype 8 gene therapy vector

2021 ◽  
Vol 20 ◽  
pp. 95-108
Author(s):  
Agostina Carestia ◽  
Seok-Joo Kim ◽  
Franziska Horling ◽  
Hanspeter Rottensteiner ◽  
Christian Lubich ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Immune Microenvironment ◽  
Adeno Associated Virus ◽  
Gene Therapy Vector ◽  
Virus Serotype

Development of Novel Cell Surface CD34-Targeted Recombinant Adenoassociated Virus Vectors for Gene Therapy

1998 ◽  
Vol 9 (13) ◽  
pp. 1929-1937 ◽  
Author(s):  
Qicheng Yang ◽  
Michael Mamounas ◽  
Gang Yu ◽  
Scott Kennedy ◽  
Brian Leaker ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Cell Surface ◽  
Virus Vectors ◽  
Adenoassociated Virus

scholarly journals Patient advocacy helps patients weigh up gene therapy trial risk/benefits

2015 ◽  
Vol 2 (1) ◽  
pp. 6-8 ◽  
Author(s):  
John Morris
Keyword(s):  
Gene Therapy ◽  
Informed Consent ◽  
Clinical Benefit ◽  
Patient Advocacy ◽  
Factor Ix ◽  
Primary Motivation ◽  
Gene Therapy Trial ◽  
Potential Risks ◽  
Adenoassociated Virus ◽  
Therapy Trial

Abstract The investigators behind the first gene therapy trial with adenoassociated virus 8 (AAV8) Factor IX appointed a patient ombudsperson to help ensure participants were able to give truly informed consent. The experiences and challenges of the ombudsperson, who met with the first six UK-based patients, are described. It was stressed to potential participants that altruism, rather than any expectation of clinical benefit, should be the primary motivation to taking part. At the same time a sober assessment of the potential risks to their safety needed to be made.

scholarly journals OneBac: Platform for Scalable and High-Titer Production of Adeno-Associated Virus Serotype 1–12 Vectors for Gene Therapy

2014 ◽  
Vol 25 (3) ◽  
pp. 212-222 ◽  
Author(s):  
Mario Mietzsch ◽  
Sabrina Grasse ◽  
Catherine Zurawski ◽  
Stefan Weger ◽  
Antonette Bennett ◽  
...  
Keyword(s):  
Gene Therapy ◽  
High Titer ◽  
Adeno Associated Virus ◽  
Virus Serotype ◽  
Serotype 1
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