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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

Adeno-associated virus (AAV) mediated transfer of Kv1.2 sense RNA for the reduction of DRG neuronal excitability. (A) Before AAV injection into the DRG of rats with peripheral nerve injury, a nerve injury-induced increase in DRG Kv1.2 AS RNA triggered by MZF1 knocks down expression of Kv1.2 mRNA and protein, resulting in an increase in DRG neuronal excitability under neuropathic pain conditions. (B) After AAV injection into the DRG of rats with peripheral nerve injury, AAV mediated transfer of full length Kv1.2 sense (SE) RNA rescues nerve injury-induced DRG Kv1.2 downregulation at the DRG neuronal membrane through not only its direct translation into Kv1.2 protein but also its indirect blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via extensive overlap of their complementary regions. AAV mediated transfer of Kv1.2 SE RNA fragment (-311 to +40) also rescues nerve injury-induced DRG Kv1.2 downregulation through its blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via partial overlap of their complementary regions, although this RNA fragment cannot be translated into Kv1.2 protein. Maintaining normal Kv1.2 expression at DRG neuronal membrane reduces nerve injury-induced neuronal hyperexcitability at DRG neurons and consequently decreases spinal central sensitization, resulting in neuropathic relief.
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Fig2: Adeno-associated virus (AAV) mediated transfer of Kv1.2 sense RNA for the reduction of DRG neuronal excitability. (A) Before AAV injection into the DRG of rats with peripheral nerve injury, a nerve injury-induced increase in DRG Kv1.2 AS RNA triggered by MZF1 knocks down expression of Kv1.2 mRNA and protein, resulting in an increase in DRG neuronal excitability under neuropathic pain conditions. (B) After AAV injection into the DRG of rats with peripheral nerve injury, AAV mediated transfer of full length Kv1.2 sense (SE) RNA rescues nerve injury-induced DRG Kv1.2 downregulation at the DRG neuronal membrane through not only its direct translation into Kv1.2 protein but also its indirect blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via extensive overlap of their complementary regions. AAV mediated transfer of Kv1.2 SE RNA fragment (-311 to +40) also rescues nerve injury-induced DRG Kv1.2 downregulation through its blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via partial overlap of their complementary regions, although this RNA fragment cannot be translated into Kv1.2 protein. Maintaining normal Kv1.2 expression at DRG neuronal membrane reduces nerve injury-induced neuronal hyperexcitability at DRG neurons and consequently decreases spinal central sensitization, resulting in neuropathic relief.

Mentions: Nerve injury-induced downregulation of DRG Kv1.2 may contribute to neuropathic pain development and maintenance. Mimicking nerve injury-induced DRG Kv1.2 downregulation reduced total Kv current, depolarized the resting membrane potential, decreased the current threshold for activation of action potentials, and increased the number of action potentials in large and medium DRG neurons [45]. Rescuing the SNL-induced downregulation of DRG Kv1.2 by blocking SNL-induced upregulation of DRG Kv1.2 AS RNA through microinjection of a AAV5 Kv1.2 sense RNA fragment (-311 to +40) into the injured DRG attenuated the induction and maintenance of SNL-induced mechanical allodynia, cold hyperalgesia and thermal hyperalgesia [45]. Moreover, overexpressing DRG Kv1.2 in the injured DRG through microinjection of AAV5 full length Kv1.2 sense RNA rescued SNL-induced downregulation of DRG Kv1.2 mRNA and protein and mitigated SNL-induced mechanical allodynia, thermal hyperalgesia, and cold hyperalgesia during both the development and maintenance phases [46]. Overexpressing DRG Kv1.2 sense RNA in the injured DRG also degraded the DRG Kv1.2 AS RNA induced by SNL through the extensive overlap of their complementary regions (Figure 2) [46]. The evidence suggests that DRG Kv1.2 is a key player in neuropathic pain genesis. Given that nerve injury-induced abnormal ectopic activity in the injured myelinated afferents is considered to be a contributor of neuropathic pain genesis [61-63], rescuing Kv1.2 downregulation through AAV mediated transfer of these two Kv1.2 sense RNAs may maintain normal resting membrane potential and diminished ectopic activity in the injured DRG neurons, resulting in reduction of primary afferent transmitter release and attenuation of spinal central sensitization formation and neuropathic pain (Figure 2). Since AAV mediated transfer of neither Kv1.2 sense RNA fragment nor full length Kv1.2 sense RNA affected basal nociceptive response, capsaicin-induced acute pain, and locomotor function [45,46], the strategy of AAV mediated transfer of Kv1.2 sense RNA may have clinical implication in neuropathic pain treatment.Figure 2


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)

Adeno-associated virus (AAV) mediated transfer of Kv1.2 sense RNA for the reduction of DRG neuronal excitability. (A) Before AAV injection into the DRG of rats with peripheral nerve injury, a nerve injury-induced increase in DRG Kv1.2 AS RNA triggered by MZF1 knocks down expression of Kv1.2 mRNA and protein, resulting in an increase in DRG neuronal excitability under neuropathic pain conditions. (B) After AAV injection into the DRG of rats with peripheral nerve injury, AAV mediated transfer of full length Kv1.2 sense (SE) RNA rescues nerve injury-induced DRG Kv1.2 downregulation at the DRG neuronal membrane through not only its direct translation into Kv1.2 protein but also its indirect blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via extensive overlap of their complementary regions. AAV mediated transfer of Kv1.2 SE RNA fragment (-311 to +40) also rescues nerve injury-induced DRG Kv1.2 downregulation through its blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via partial overlap of their complementary regions, although this RNA fragment cannot be translated into Kv1.2 protein. Maintaining normal Kv1.2 expression at DRG neuronal membrane reduces nerve injury-induced neuronal hyperexcitability at DRG neurons and consequently decreases spinal central sensitization, resulting in neuropathic relief.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Fig2: Adeno-associated virus (AAV) mediated transfer of Kv1.2 sense RNA for the reduction of DRG neuronal excitability. (A) Before AAV injection into the DRG of rats with peripheral nerve injury, a nerve injury-induced increase in DRG Kv1.2 AS RNA triggered by MZF1 knocks down expression of Kv1.2 mRNA and protein, resulting in an increase in DRG neuronal excitability under neuropathic pain conditions. (B) After AAV injection into the DRG of rats with peripheral nerve injury, AAV mediated transfer of full length Kv1.2 sense (SE) RNA rescues nerve injury-induced DRG Kv1.2 downregulation at the DRG neuronal membrane through not only its direct translation into Kv1.2 protein but also its indirect blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via extensive overlap of their complementary regions. AAV mediated transfer of Kv1.2 SE RNA fragment (-311 to +40) also rescues nerve injury-induced DRG Kv1.2 downregulation through its blockage of nerve injury-induced increase in Kv1.2 AS RNA expression via partial overlap of their complementary regions, although this RNA fragment cannot be translated into Kv1.2 protein. Maintaining normal Kv1.2 expression at DRG neuronal membrane reduces nerve injury-induced neuronal hyperexcitability at DRG neurons and consequently decreases spinal central sensitization, resulting in neuropathic relief.
Mentions: Nerve injury-induced downregulation of DRG Kv1.2 may contribute to neuropathic pain development and maintenance. Mimicking nerve injury-induced DRG Kv1.2 downregulation reduced total Kv current, depolarized the resting membrane potential, decreased the current threshold for activation of action potentials, and increased the number of action potentials in large and medium DRG neurons [45]. Rescuing the SNL-induced downregulation of DRG Kv1.2 by blocking SNL-induced upregulation of DRG Kv1.2 AS RNA through microinjection of a AAV5 Kv1.2 sense RNA fragment (-311 to +40) into the injured DRG attenuated the induction and maintenance of SNL-induced mechanical allodynia, cold hyperalgesia and thermal hyperalgesia [45]. Moreover, overexpressing DRG Kv1.2 in the injured DRG through microinjection of AAV5 full length Kv1.2 sense RNA rescued SNL-induced downregulation of DRG Kv1.2 mRNA and protein and mitigated SNL-induced mechanical allodynia, thermal hyperalgesia, and cold hyperalgesia during both the development and maintenance phases [46]. Overexpressing DRG Kv1.2 sense RNA in the injured DRG also degraded the DRG Kv1.2 AS RNA induced by SNL through the extensive overlap of their complementary regions (Figure 2) [46]. The evidence suggests that DRG Kv1.2 is a key player in neuropathic pain genesis. Given that nerve injury-induced abnormal ectopic activity in the injured myelinated afferents is considered to be a contributor of neuropathic pain genesis [61-63], rescuing Kv1.2 downregulation through AAV mediated transfer of these two Kv1.2 sense RNAs may maintain normal resting membrane potential and diminished ectopic activity in the injured DRG neurons, resulting in reduction of primary afferent transmitter release and attenuation of spinal central sensitization formation and neuropathic pain (Figure 2). Since AAV mediated transfer of neither Kv1.2 sense RNA fragment nor full length Kv1.2 sense RNA affected basal nociceptive response, capsaicin-induced acute pain, and locomotor function [45,46], the strategy of AAV mediated transfer of Kv1.2 sense RNA may have clinical implication in neuropathic pain treatment.Figure 2

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