An animal model study found promising results for a precision spinal gene therapy for reversing neuropathic pain. These findings were published in Molecular Therapy.
In this study, a technique involving subpial dorsal horn-targeted delivery of an adeno-associated viral (AAV) vector with a gamma-aminobutyric acid (GABA) synthesizing-releasing inhibitory machinery was evaluated. Neuropathic pain was induced in mice using a sciatic nerve ligation approach. Efficacy of the targeted delivery was evaluated in mice, and safety was evaluated in pigs and nonhuman primates.
Unilateral injection into the L3-L5 subpial space was found to be an effective delivery method, leading to widespread induced gene expression in the contralateral side of the ventral horn.
The primary efficacy endpoints were changes to paw tactile withdrawal response and brush-evoked pain response. The mice that experienced peripheral nerve injury and received treatment with 2 gene vectors for glutamate decarboxylase 2 (GAD65) and vesicular GABA transporter (VGAT) demonstrated an improved injury-associated tactile withdrawal threshold starting 1 week after treatment (P =.0125) and improving at week 2 (P =.0002). Similarly, brush-evoked allodynia returned to levels comparable with those seen in control mice 2 weeks after treatment (P =.0003).
The mice treated with the 2 gene vectors were found to have a decrease in the proportion of neurons with evoked spiking compared with wild-type mice (P =.013), and the proportion of neurons without excitatory responses (P =.008) and with inhibitory responses (P =.0005) increased.
Mice that received AAV-delivered ubiquitin C (UBC)-GAD65/VGAT gene therapy were found to have similar responses as mice that received the 2 gene vectors, with tactile withdrawal response improving at 2 weeks after treatment (P =.0149) and improving further at 3 weeks (P =.0056). Similarly, brush-evoked allodynia responses improved at 2 (P =.0007), 4 (P =.0008), and 6 (P =.0009) weeks after treatment.
A comparative analysis was performed to evaluate the dosing volume and safety in pigs and nonhuman primates. The investigators found that subpial delivery using a surgical approach and injection device appeared to be safe at 2 months after treatment.
It remains unclear whether this therapy could be translated to humans and whether it may be safe and effective at reducing neuropathic symptoms.
“In summary, we demonstrate that the spinal-unilateral subpial delivery of GAD65 and VGAT genes is highly effective in providing a potent and long-lasting reversal of [peripheral nerve injury]-induced neuropathic pain. The mechanism of this anti-nociceptive effect is the result of the induced neurotransmitter-phenotypic switch from excitatory to inhibitory in dorsal horn nociceptive neurons,” stated the study authors. “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.”
Disclosure: One study author declared an affiliation with industry. Please refer to the original article for a full list of disclosures.
References:
Tadokoro T, Bravo-Hernandez M, Agashkov K, et al. Precision spinal gene delivery-induced functional switch in nociceptive neurons reverses neuropathic pain. Mol Ther. 2022;S1525-0016(22)00294-5. doi:10.1016/j.ymthe.2022.04.023