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Current gene therapy using viral vectors for chronic pain.

Guedon JM, Wu S, Zheng X, Churchill CC, Glorioso JC, Liu CH, Liu S, Vulchanova L, Bekker A, Tao YX, Kinchington PR, Goins WF, Fairbanks CA, Hao S - Mol Pain (2015)

Bottom Line: Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery.Fairbanks and S.Hao).

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Molecular Virology and Microbiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15213, USA. jmguedon@gmail.com.

ABSTRACT
The complexity of chronic pain and the challenges of pharmacotherapy highlight the importance of development of new approaches to pain management. Gene therapy approaches may be complementary to pharmacotherapy for several advantages. Gene therapy strategies may target specific chronic pain mechanisms in a tissue-specific manner. The present collection of articles features distinct gene therapy approaches targeting specific mechanisms identified as important in the specific pain conditions. Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery. Dr. Tao group addresses that downregulation of a voltage-gated potassium channel (Kv1.2) contributes to the maintenance of neuropathic pain. Alleviation of chronic pain through restoring Kv1.2 expression in sensory neurons is presented in this review. Drs Goins and Kinchington group describes a strategy to use the replication defective HSV vector to deliver two different gene products (enkephalin and TNF soluble receptor) for the treatment of post-herpetic neuralgia. Dr. Hao group addresses the observation that the pro-inflammatory cytokines are an important shared mechanism underlying both neuropathic pain and the development of opioid analgesic tolerance and withdrawal. The use of gene therapy strategies to enhance expression of the anti-pro-inflammatory cytokines is summarized. Development of multiple gene therapy strategies may have the benefit of targeting specific pathologies associated with distinct chronic pain conditions (by Guest Editors, Drs. C. Fairbanks and S. Hao).

No MeSH data available.


Related in: MedlinePlus

Nerve injury-induced Kv1.2 downregulation triggered by myeloid zinc finger protein 1 (MZF1)-mediated Kv1.2 antisense (AS) RNA expression in the injured dorsal root ganglion (DRG). (A) Under normal conditions, Kv1.2 mRNA that is transcribed from the genome is translated into Kv1.2 protein, resulting in normal expression of Kv1.2 channel at DRG neuronal membrane. (B) Under neuropathic pain conditions, peripheral nerve injury promotes the expression of the transcription factor MZF1 in DRG. The increased MZF1 binds to the promoter region of Kv1.2 AS RNA gene and triggers its expression. The latter specifically and selectively inhibits the expression of Kv1.2 mRNA via extensive overlap of their complementary regions, leading to a reduction in the membrane expression of Kv1.2 only, not other Kv subunits (e.g., Kv1.1), in the DRG neurons.
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Fig1: Nerve injury-induced Kv1.2 downregulation triggered by myeloid zinc finger protein 1 (MZF1)-mediated Kv1.2 antisense (AS) RNA expression in the injured dorsal root ganglion (DRG). (A) Under normal conditions, Kv1.2 mRNA that is transcribed from the genome is translated into Kv1.2 protein, resulting in normal expression of Kv1.2 channel at DRG neuronal membrane. (B) Under neuropathic pain conditions, peripheral nerve injury promotes the expression of the transcription factor MZF1 in DRG. The increased MZF1 binds to the promoter region of Kv1.2 AS RNA gene and triggers its expression. The latter specifically and selectively inhibits the expression of Kv1.2 mRNA via extensive overlap of their complementary regions, leading to a reduction in the membrane expression of Kv1.2 only, not other Kv subunits (e.g., Kv1.1), in the DRG neurons.

Mentions: Myeloid zinc finger gene 1 (MZF1), a transcription factor, triggers the activation of Kv1.2 AS RNA gene expression in the injured DRG following peripheral nerve injury. Kv1.2 AS RNA gene promoter contains a consensus MZF1-binding motif (-161 to -154). Once bound to this motif, MZF1 promots transcription of target genes [64,65]. In DRG, MZF1 was reported to bind to this motif on the Kv1.2 AS gene promoter [45]. SNL time-dependently increased MZF1 expression and its binding activity in the injured DRG [45]. Moreover, MZF1 directly promoted Kv1.2 AS gene transcriptional activity and was co-expressed with Kv1.2 AS RNA in DRG neurons [45]. It is very likely that nerve injury-induced downregulation of DRG Kv1.2 mRNA is attributed to MZF1-triggered upregulation of DRG Kv1.2 AS RNA under neuropathic pain conditions (FigureĀ 1). It is worth noting that the nerve injury-induced decrease in Kv1.2 mRNA and protein might be caused by other mechanisms at transcriptional and translational levels. These mechanisms will be addressed in future studies.Figure 1


Current gene therapy using viral vectors for chronic pain.

Guedon JM, Wu S, Zheng X, Churchill CC, Glorioso JC, Liu CH, Liu S, Vulchanova L, Bekker A, Tao YX, Kinchington PR, Goins WF, Fairbanks CA, Hao S - Mol Pain (2015)

Nerve injury-induced Kv1.2 downregulation triggered by myeloid zinc finger protein 1 (MZF1)-mediated Kv1.2 antisense (AS) RNA expression in the injured dorsal root ganglion (DRG). (A) Under normal conditions, Kv1.2 mRNA that is transcribed from the genome is translated into Kv1.2 protein, resulting in normal expression of Kv1.2 channel at DRG neuronal membrane. (B) Under neuropathic pain conditions, peripheral nerve injury promotes the expression of the transcription factor MZF1 in DRG. The increased MZF1 binds to the promoter region of Kv1.2 AS RNA gene and triggers its expression. The latter specifically and selectively inhibits the expression of Kv1.2 mRNA via extensive overlap of their complementary regions, leading to a reduction in the membrane expression of Kv1.2 only, not other Kv subunits (e.g., Kv1.1), in the DRG neurons.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4446851&req=5

Fig1: Nerve injury-induced Kv1.2 downregulation triggered by myeloid zinc finger protein 1 (MZF1)-mediated Kv1.2 antisense (AS) RNA expression in the injured dorsal root ganglion (DRG). (A) Under normal conditions, Kv1.2 mRNA that is transcribed from the genome is translated into Kv1.2 protein, resulting in normal expression of Kv1.2 channel at DRG neuronal membrane. (B) Under neuropathic pain conditions, peripheral nerve injury promotes the expression of the transcription factor MZF1 in DRG. The increased MZF1 binds to the promoter region of Kv1.2 AS RNA gene and triggers its expression. The latter specifically and selectively inhibits the expression of Kv1.2 mRNA via extensive overlap of their complementary regions, leading to a reduction in the membrane expression of Kv1.2 only, not other Kv subunits (e.g., Kv1.1), in the DRG neurons.
Mentions: Myeloid zinc finger gene 1 (MZF1), a transcription factor, triggers the activation of Kv1.2 AS RNA gene expression in the injured DRG following peripheral nerve injury. Kv1.2 AS RNA gene promoter contains a consensus MZF1-binding motif (-161 to -154). Once bound to this motif, MZF1 promots transcription of target genes [64,65]. In DRG, MZF1 was reported to bind to this motif on the Kv1.2 AS gene promoter [45]. SNL time-dependently increased MZF1 expression and its binding activity in the injured DRG [45]. Moreover, MZF1 directly promoted Kv1.2 AS gene transcriptional activity and was co-expressed with Kv1.2 AS RNA in DRG neurons [45]. It is very likely that nerve injury-induced downregulation of DRG Kv1.2 mRNA is attributed to MZF1-triggered upregulation of DRG Kv1.2 AS RNA under neuropathic pain conditions (FigureĀ 1). It is worth noting that the nerve injury-induced decrease in Kv1.2 mRNA and protein might be caused by other mechanisms at transcriptional and translational levels. These mechanisms will be addressed in future studies.Figure 1

Bottom Line: Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery.Fairbanks and S.Hao).

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Molecular Virology and Microbiology, University of Pittsburgh, School of Medicine, Pittsburgh, PA, 15213, USA. jmguedon@gmail.com.

ABSTRACT
The complexity of chronic pain and the challenges of pharmacotherapy highlight the importance of development of new approaches to pain management. Gene therapy approaches may be complementary to pharmacotherapy for several advantages. Gene therapy strategies may target specific chronic pain mechanisms in a tissue-specific manner. The present collection of articles features distinct gene therapy approaches targeting specific mechanisms identified as important in the specific pain conditions. Dr. Fairbanks group describes commonly used gene therapeutics (herpes simplex viral vector (HSV) and adeno-associated viral vector (AAV)), and addresses biodistribution and potential neurotoxicity in pre-clinical models of vector delivery. Dr. Tao group addresses that downregulation of a voltage-gated potassium channel (Kv1.2) contributes to the maintenance of neuropathic pain. Alleviation of chronic pain through restoring Kv1.2 expression in sensory neurons is presented in this review. Drs Goins and Kinchington group describes a strategy to use the replication defective HSV vector to deliver two different gene products (enkephalin and TNF soluble receptor) for the treatment of post-herpetic neuralgia. Dr. Hao group addresses the observation that the pro-inflammatory cytokines are an important shared mechanism underlying both neuropathic pain and the development of opioid analgesic tolerance and withdrawal. The use of gene therapy strategies to enhance expression of the anti-pro-inflammatory cytokines is summarized. Development of multiple gene therapy strategies may have the benefit of targeting specific pathologies associated with distinct chronic pain conditions (by Guest Editors, Drs. C. Fairbanks and S. Hao).

No MeSH data available.


Related in: MedlinePlus