Tadokoro, Takahiro;
Bravo-Hernandez, Mariana;
Agashkov, Kirill;
Kobayashi, Yoshiomi;
Platoshyn, Oleksandr;
Navarro, Michael;
Marsala, Silvia;
... Marsala, Martin; + view all
(2022)
Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain.
Molecular Therapy
, 30
(8)
pp. 2722-2745.
10.1016/j.ymthe.2022.04.023.
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Abstract
Second-order spinal cord excitatory neurons play a key role in spinal processing and transmission of pain signals to the brain. Exogenously induced change in developmentally imprinted excitatory neurotransmitter phenotypes of these neurons to inhibitory has not yet been achieved. Here, we use a subpial dorsal horn-targeted delivery of AAV (adeno-associated virus) vector(s) encoding GABA (gamma-aminobutyric acid) synthesizing-releasing inhibitory machinery in mice with neuropathic pain. Treated animals showed a progressive and complete reversal of neuropathic pain (tactile and brush-evoked pain behavior) that persisted for a minimum of 2.5 months post-treatment. The mechanism of this treatment effect results from the switch of excitatory to preferential inhibitory neurotransmitter phenotype in dorsal horn nociceptive neurons and a resulting increase in inhibitory activity in regional spinal circuitry after peripheral nociceptive stimulation. No detectable side effects (e.g., sedation, motor weakness, loss of normal sensation) were seen between 2 and 13 months post-treatment in naive adult mice, pigs, and non-human primates. The use of this treatment approach may represent a potent and safe treatment modality in patients suffering from spinal cord or peripheral nerve injury-induced neuropathic pain.
| Type: | Article |
|---|---|
| Title: | Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ymthe.2022.04.023 |
| Publisher version: | https://doi.org/10.1016/j.ymthe.2022.04.023 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher's terms and conditions. |
| Keywords: | neuropathic pain, GAD65 and VGAT, subpial injection technique, targeted AAV9 delivery, long-lasting pain reversal, precision spinal vector delivery, subpial pig, subpial non-human primates |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Neuro, Physiology and Pharmacology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10173234 |
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