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AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain

Gene Therapy volume 26, pages 308–323 (2019)Cite this article

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Abstract

Transmission of pain signals from primary sensory neurons to secondary neurons of the central nervous system is critically dependent on presynaptic voltage-gated calcium channels. Calcium channel-binding domain 3 (CBD3), derived from the collapsin response mediator protein 2 (CRMP2), is a peptide aptamer that is effective in blocking N-type voltage-gated calcium channel (CaV2.2) activity. We previously reported that recombinant adeno-associated virus (AAV)-mediated restricted expression of CBD3 affixed to enhanced green fluorescent protein (EGFP) in primary sensory neurons prevents the development of cutaneous mechanical hypersensitivity in a rat neuropathic pain model. In this study, we tested whether this strategy is effective in treating established pain. We constructed AAV6-EGFP-CBD3A6K (AAV6-CBD3A6K) expressing a fluorescent CBD3A6K (replacing A to K at position 6 of CBD3 peptide), which is an optimized variant of the parental CBD3 peptide that is a more potent blocker of CaV2.2. Delivery of AAV6-CBD3A6K into lumbar (L) 4 and 5 dorsal root ganglia (DRG) of rats 2 weeks following tibial nerve injury (TNI) induced transgene expression in neurons of these DRG and their axonal projections, accompanied by attenuation of pain behavior. We additionally observed that the increased CaV2.2α1b immunoreactivity in the ipsilateral spinal cord dorsal horn and DRG following TNI was significantly normalized by AAV6-CBD3A6K treatment. Finally, the increased neuronal activity in the ipsilateral dorsal horn that developed after TNI was reduced by AAV6-CBD3A6K treatment. Collectively, these results indicate that DRG-restricted AAV6 delivery of CBD3A6K is an effective analgesic molecular strategy for the treatment of established neuropathic pain.

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Acknowledgements

This research was supported by a grant from the Department of Veterans Affairs Rehabilitation Research and Development I01RX001940 (to Q. Hogan). R. Khanna is supported by grants from National Institutes of Health Awards (1R01NS098772 and 1R01DA042852). H. Xiang was a recipient of National Natural Science Foundation of China (81802190, 81772412). Y. Cai was a recipient of Chinese Scholarship Council.

Author information

Authors and Affiliations

  1. Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, WI, 53226, USA

    Hongwei Yu, Seung Min Shin, Hongfei Xiang, Dongman Chao, Yongsong Cai, Hao Xu, Bin Pan & Quinn H. Hogan

  2. Zablocki Veterans Affairs Medical Center, Milwaukee, WI, 53295, USA

    Hongwei Yu, Seung Min Shin & Quinn H. Hogan

  3. Department of Orthopedic Surgery, Affiliated Hospital of Qingdao University, 266000, Qingdao, PR China

    Hongfei Xiang & Hao Xu

  4. Xi’an Jiaotong University Health Science Center, 710061, Xi’an, Shaanxi, PR China

    Yongsong Cai

  5. Departments of Pharmacology, Neuroscience and Anesthesiology, College of Medicine, University of Arizona, Tucson, AZ, 85724, USA

    Rajesh Khanna

Authors
  1. Hongwei Yu
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  2. Seung Min Shin
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  3. Hongfei Xiang
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  4. Dongman Chao
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  5. Yongsong Cai
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  6. Hao Xu
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  7. Rajesh Khanna
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  8. Bin Pan
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  9. Quinn H. Hogan
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Correspondence to Hongwei Yu.

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Yu, H., Shin, S., Xiang, H. et al. AAV-encoded CaV2.2 peptide aptamer CBD3A6K for primary sensory neuron-targeted treatment of established neuropathic pain. Gene Ther 26, 308–323 (2019). https://doi.org/10.1038/s41434-019-0082-7

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  • DOI: https://doi.org/10.1038/s41434-019-0082-7

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