AAV8gfp preferentially targets large diameter dorsal root ganglion neurones after both intra-dorsal root ganglion and intrathecal injection

Jacques, Steven J.; Ahmed, Zubair; Forbes, Anna; Douglas, Michael E.; Vigenswara, Vasanthy; Berry, Martin; Logan, Ann

doi:10.1016/j.mcn.2012.03.002

Cited by 58 publications

(72 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, none of those previous studies focused specifically on myelinating Schwann cells, because ubiquitous promoters were used. Widespread expression was reported in some cases after AAV injection from the spinal cord to the brain in both adults and neonates (26,33), and even after AAV9 injection in large animal models (27,34). This is the first demonstration, to our knowledge, of a successful intrathecal approach to treating peripheral neuropathy by delivering a myelin-related gene and achieving widespread Schwann cell-specific expression.…”

Section: Discussionmentioning

confidence: 72%

“…This is in keeping with our previous observations following intraneural delivery of the same vector (8) or with preclinical (37,38) and clinical (39) applications of similar lentiviral vectors. Rarely reported inflammatory responses (26) were attributed to the reporter gene and not to the intrathecal method of gene delivery or to the vector type.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inherited demyelinating peripheral neuropathies are progressive incurable diseases without effective treatment. To develop a gene therapy approach targeting myelinating Schwann cells that can be translatable, we delivered a lentiviral vector using a single lumbar intrathecal injection and a myelin-specific promoter. The human gene of interest, GJB1, which is mutated in X-linked CharcotMarie-Tooth Disease (CMT1X), was delivered intrathecally into adult Gjb1-null mice, a genetically authentic model of CMT1X that develops a demyelinating peripheral neuropathy. We obtained widespread, stable, and cell-specific expression of connexin32 in up to 50% of Schwann cells in multiple lumbar spinal roots and peripheral nerves. Behavioral and electrophysiological analysis revealed significantly improved motor performance, quadriceps muscle contractility, and sciatic nerve conduction velocities. Furthermore, treated mice exhibited reduced numbers of demyelinated and remyelinated fibers and fewer inflammatory cells in lumbar motor roots, as well as in the femoral motor and sciatic nerves. This study demonstrates that a single intrathecal lentiviral gene delivery can lead to Schwann cell-specific expression in spinal roots extending to multiple peripheral nerves. This clinically relevant approach improves the phenotype of an inherited neuropathy mouse model and provides proof of principle for treating inherited demyelinating neuropathies.demyelinating neuropathy | Charcot-Marie-Tooth disease | connexin32 | peripheral nerve | gene therapy

show abstract

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Kagiava

Sargiannidou

Theophilidis

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Intrathecal AAV8 shows a similar propensity in rats (Storek et al, 2008;Jacques et al, 2012). That NHP DRGs are accessible by AAV7 and AAV9 suggests utility for these serotypes in transducing DRG.…”

Section: Figmentioning

confidence: 89%

“…That NHP DRGs are accessible by AAV7 and AAV9 suggests utility for these serotypes in transducing DRG. Given the central role DRG play in transmission of pain signals and maintenance of pathological pain, both AAV2 (Milligan et al, 2005) and AAV8 (Storek et al, 2008;Jacques et al, 2012) have been used to therapeutic effect in rat models of neuropathic pain. Clearly, this area is ripe for a more intensive survey of other AAV serotypes in terms of efficiency and specificity.…”

Section: Figmentioning

confidence: 99%

Strong Cortical and Spinal Cord Transduction After AAV7 and AAV9 Delivery into the Cerebrospinal Fluid of Nonhuman Primates

Samaranch

Salegio²,

Sebastián³

et al. 2013

Human Gene Therapy

133

136

View full text Add to dashboard Cite

The present study builds on previous work showing that infusion of adeno-associated virus type 9 (AAV9) into the cisterna magna (CM) of nonhuman primates resulted in widespread transduction throughout cortex and spinal cord. Transduction efficiency was severely limited, however, by the presence of circulating anti-AAV antibodies. Accordingly, we compared AAV9 to a related serotype, AAV7, which has a high capsid homology. CM infusion of either AAV7 or AAV9 directed high level of cell transduction with similar patterns of distribution throughout brain cortex and along the spinal cord. Dorsal root ganglia and corticospinal tracts were also transduced. Both astrocytes and neurons were transduced. Interestingly, little transduction was observed in peripheral organs. Our results indicate that intrathecal delivery of either AAV7 or AAV9 directs a robust and widespread cellular transduction in the central nervous system and other peripheral neural structures.

show abstract

“…The rAAV6-delivered gene and the TrkA receptor were co-labeled; thus, we knocked down STX8 expression in rat DRG neurons by rAAV6-mediated RNA interference. Meanwhile, rAAV8 is considered to preferentially target large diameter DRG neurons (33,34), so we used rAAV8 as a control to infect TrkA-negative neurons. rAAV6-siSTX8-ZsGreen and rAAV8-siSTX8-GFP were intrathecally injected into the cerebrospinal fluid through the L4/5 intervertebral space.…”

Section: Stx8 Depletion In Trka-positive Drg Neurons Relieves Inflammmentioning

confidence: 99%

Syntaxin 8 Modulates the Post-synthetic Trafficking of the TrkA Receptor and Inflammatory Pain Transmission*

Chen

Zhao

et al. 2014

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background:Proper cell surface location of TrkA is crucial for NGF-mediated functions; however, the mechanisms modulating TrkA surface levels remain unclear. Results: Syntaxin 8 increases TrkA surface levels and modulates inflammatory pain transmission. Conclusion: Syntaxin 8-regulated TrkA surface targeting is essential for NGF-mediated functions. Significance: These findings advance our understanding of the mechanisms of TrkA surface targeting and pain transmission.

show abstract

AAV8gfp preferentially targets large diameter dorsal root ganglion neurones after both intra-dorsal root ganglion and intrathecal injection

Cited by 58 publications

References 49 publications

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Intrathecal gene therapy rescues a model of demyelinating peripheral neuropathy

Strong Cortical and Spinal Cord Transduction After AAV7 and AAV9 Delivery into the Cerebrospinal Fluid of Nonhuman Primates

Syntaxin 8 Modulates the Post-synthetic Trafficking of the TrkA Receptor and Inflammatory Pain Transmission*

Contact Info

Product

Resources

About