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 Adeno-associated virus Rep proteins antagonize phosphatase PP1 to counteract KAP1 repression of the latent viral genome

2018 ◽  
Vol 115 (15) ◽  
pp. E3529-E3538 ◽  
Author(s):  
Sarah Smith-Moore ◽  
Stuart J. D. Neil ◽  
Cornel Fraefel ◽  
R. Michael Linden ◽  
Mathieu Bollen ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Helper Virus ◽  
Protein Phosphatase 1 ◽  
Wild Type ◽  
Fha Domain ◽  
Adeno Associated Virus ◽  
Histone 3 ◽  
Rep Proteins ◽  
Cellular Factors

Adeno-associated virus (AAV) is a small human Dependovirus whose low immunogenicity and capacity for long-term persistence have led to its widespread use as vector for gene therapy. Despite great recent successes in AAV-based gene therapy, further improvements in vector technology may be hindered by an inadequate understanding of various aspects of basic AAV biology. AAV is unique in that its replication is largely dependent on a helper virus and cellular factors. In the absence of helper virus coinfection, wild-type AAV establishes latency through mechanisms that are not yet fully understood. Challenging the currently held model for AAV latency, we show here that the corepressor Krüppel-associated box domain-associated protein 1 (KAP1) binds the latent AAV2 genome at the rep ORF, leading to trimethylation of AAV2-associated histone 3 lysine 9 and that the inactivation of KAP1 repression is necessary for AAV2 reactivation and replication. We identify a viral mechanism for the counteraction of KAP1 in which interference with the KAP1 phosphatase protein phosphatase 1 (PP1) by the AAV2 Rep proteins mediates enhanced phosphorylation of KAP1-S824 and thus relief from KAP1 repression. Furthermore, we show that this phenomenon involves recruitment of the NIPP1 (nuclear inhibitor of PP1)–PP1α holoenzyme to KAP1 in a manner dependent upon the NIPP1 FHA domain, identifying NIPP1 as an interaction partner for KAP1 and shedding light on the mechanism through which PP1 regulates cellular KAP1 activity.

scholarly journals Planet of the AAVs: The Spinal Cord Injury Episode

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 613
Author(s):  
Katerina Stepankova ◽  
Pavla Jendelova ◽  
Lucia Machova Urdzikova
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Spinal Cord Injury ◽  
Cell Types ◽  
Specific Cell ◽  
Adeno Associated Virus ◽  
Adequate Treatment ◽  
Cord Injury ◽  
The Central Nervous System ◽  
Transgene Delivery

The spinal cord injury (SCI) is a medical and life-disrupting condition with devastating consequences for the physical, social, and professional welfare of patients, and there is no adequate treatment for it. At the same time, gene therapy has been studied as a promising approach for the treatment of neurological and neurodegenerative disorders by delivering remedial genes to the central nervous system (CNS), of which the spinal cord is a part. For gene therapy, multiple vectors have been introduced, including integrating lentiviral vectors and non-integrating adeno-associated virus (AAV) vectors. AAV vectors are a promising system for transgene delivery into the CNS due to their safety profile as well as long-term gene expression. Gene therapy mediated by AAV vectors shows potential for treating SCI by delivering certain genetic information to specific cell types. This review has focused on a potential treatment of SCI by gene therapy using AAV vectors.

Adeno-associated virus packaged TRPC5 gene therapy alleviated spinal cord ischemic reperfusion injury in rats

Neuroreport ◽  
2020 ◽  
Vol 31 (1) ◽  
pp. 29-36
Author(s):  
Nana Shen ◽  
Lin Wang ◽  
Yiling Wu ◽  
Yanlin Liu ◽  
Haitao Pei ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Reperfusion Injury ◽  
Ischemic Reperfusion Injury ◽  
Adeno Associated Virus ◽  
Ischemic Reperfusion

Adeno-Associated Viral Vectors for Gene Transfer and Gene Therapy

1999 ◽  
Vol 380 (6) ◽  
Author(s):  
H. Büeler
Keyword(s):  
Gene Expression ◽  
Gene Therapy ◽  
Gene Transfer ◽  
Gene Delivery ◽  
Viral Vectors ◽  
Delivery Systems ◽  
Adeno Associated Virus ◽  
Viral Genes ◽  
Virus Recombinant

AbstractAdeno-associated virus (AAV) is a defective, non-pathogenic human parvovirus that depends for growth on coinfection with a helper adenovirus or herpes virus. Recombinant adeno-associated viruses (rAAVs) have attracted considerable interest as vectors for gene therapy. In contrast to other gene delivery systems, rAAVs lack all viral genes and show long-term gene expression

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 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
Sign in / Sign up

Export Citation Format

Share Document