654. Recombinant Gene and Cell Therapy With Serine-Histogranin and Endomorphin-1 for the Experimental Treatment of Chronic Neuropathic Pain

Jergová, Stanislava; Gordon, Charles A.; Gajavelli, Shyam; Sagen, Jacqueline

doi:10.1016/s1525-0016(16)34263-0

Cited by 1 publication

(3 citation statements)

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“…Multimeric 6SHG constructs resulted in more stable attenuation of tactile allodynia and stable and robust reversal of heat hyperalgesia following peripheral nerve injury. These results are in agreement with our previous observation of enhanced analgesic efficacy of multi-SHG constructs compared to the single SHG (33,34). It has been suggested that the variability of the analgesic efficacy of the SHG construct observed in different behavioral tests may be related to its physiological properties, such as modulation of other receptors, including NK1 and dopamine (27,30,39,4).…”

Section: Discussionsupporting

confidence: 93%

“…We have previously generated lenti-SHG constructs, which resulted in successful production of SHG peptide in a variety of cell types (18). To increase the antinociceptive potential of the construct in latter studies, we engineered SHG multimers to generate up to six copies of the SHG peptide (34,36). The AAV 2/8 hybrid vector was chosen for engineering of recombinant viral particles based on our screenings of different AAV serotypes as the most efficient serotype for transduction of neuronal cells.…”

Section: Methodsmentioning

confidence: 99%

“…Such an approach is supported by pharmacological observations using a multitargeting approach, whereby enhanced analgesia is achieved by a subthreshold amount of drugs in proper combinations (24–26). Simultaneous targeting of different pain pathways by analgesic peptides delivered via gene therapy using viral vectors also yielded promising results for chronic pain management (33,34,43). The aim of this study was to therefore evaluate the potential of a novel approach using gene engineering and generation of recombinant GABAergic cells releasing Serine 1 -histogranin (SHG) as an additional analgesic peptide.…”

Section: Introductionmentioning

confidence: 99%

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Analgesic Effect of Recombinant GABAergic Cells in a Model of Peripheral Neuropathic Pain

et al. 2016

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Chronic neuropathic pain represents a clinically challenging state with a poor response to current treatment options. Long-term management of chronic pain is often associated with the development of tolerance, addiction, and other side effects, reducing the therapeutic value of treatment. Alternative strategies based on cell therapy and gene manipulation, balancing the inhibitory and excitatory events in the spinal cord, may provide sustained pain relief in the long term. Transplantation of GABAergic cells has been successfully used to enhance inhibition and to restore physiological spinal pain processing. However, since the underlying mechanism of chronic pain development involves changes in several pain-signaling pathways, it is essential to develop an approach that targets several components of pain signaling. Recombinant cell therapy offers the possibility to deliver additional analgesic substances to the restricted area in the nervous system. The current study explores the analgesic potential of genetically modified rat embryonic GABAergic cells releasing a peptidergic NMDA receptor antagonist, Serine 1 -histogranin (SHG). Overactivation of glutamate NMDA receptors contributes to the hyperexcitability of spinal neurons observed in chronic pain models. Our approach allows us to simultaneously target spinal hyperexcitability and reduced inhibitory processes. Transplantable cells were transduced by viral vectors encoding either one or six copies of SHG cDNAs. The analgesic potential of recombinant cells after their intraspinal transplantation was evaluated in a model of peripheral nerve injury. Enhanced reduction of hypersensitivity to thermal and mechanical stimuli was observed in animals treated by recombinant cells compared to the nonrecombinant group. The recombinant peptide was detected in the spinal tissue, suggesting its successful production by transplanted cells. Our results demonstrate the feasibility of using recombinant cells releasing adjunct analgesic peptides in the therapy of neuropathic pain.

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